Phenoxyalkylamine derivatives useful as opioid receptor agonists

ABSTRACT

A medicament useful for preventive and/or therapeutic treatment of nerve system diseases which comprises, as an active ingredient, a compound represented by the following general formula (I) or a pharmacologically acceptable salt thereof:  
                 
 
     wherein, X represents a group represented by the following general formula (II), (III), (IV), (V), or (VI),  
                 
 
     “A” represents a saturated or unsaturated 3- to 6-membered carbocyclic group and the like, “B” represents CH 2  and the like, “n” represents 0 to 2, R 1  represents a hydrogen atom, a halogen atom and the like, R 2 , R 3 , and R 7  to R 14  represent a hydrogen atom, a lower alkyl group which may be substituted and the like, R 4  represents a hydrogen atom, a lower alkyl group which may be substituted and the like, R 5  represents a hydrogen atom, a halogen atom and the like, R 6  represents a saturated or unsaturated monocyclic or bicyclic carbocyclic group and the like, and R 5  and R 6 , R 7  and R 8 , R 9  and R 10 , or R 11  and R 12  may bind to each other to form a cyclic structure.

TECHNICAL FIELD

[0001] The present invention relates to phenoxyalkylamine derivatives,which have affinity for the opioid δ receptor and are useful in themedicinal field, and relates to medicaments comprising said compounds asan active ingredient.

BACKGROUND ART

[0002] Opioid receptors are mainly classified into three types, i.e., μ,δ and κ from a viewpoint of differences in pharmacological actions. Onthe basis of the discovery of an endogenous opioid peptide in 1970's,some progresses were made in studies about their mechanism of action. In1990's, studies about opioid receptor structures advanced based ongenetic analysis, and their mchanism of action has been being elucidatedby the molecular biology. As also for the δ receptor, based on thesuccess of cloning of δ receptor by Evans, Kieffer et al. in 1992, manystudies have been vigorously performed in the medicinal andpharmaceutical fields by the molecular biology.

[0003] Although higher order functions of the opioid δ receptors havenot yet been successfully elucidated, those already reported includethat an opioid δ receptor agonist exhibits analgesic activity (D. E.Moulin et al., Pain, 1985, 23, 213), and that the opioid δ receptoragonist has an reducing effect on adverse reactions induced by an opioidμ receptor agonist and an opioid κ receptor agonist (Gallingan et. al.,J. Pharm. Exp. Ther. 1984, 229, 641). Since the opioid δ receptor isknown to be present widely in the central and peripheral nerve systemsand considered to have a wide variety of functions, discovery of aneffective and selective opioid δ receptor ligands can greatly contributeto therapeutic treatments of central nerve system diseases includingschizophrenia, depression, cerebral apoplexy, epilepsy, Alzheimer'sdisease, and Parkinson's disease, and peripheral nerve system diseasesincluding pains (Exp. Opin. ther. Patents, 1999, 9, 353).

[0004] Compounds related to the general formula (I) of the presentinvention are reported in J. Med. Chem. 1994, 37, 2125, WO93/15062,WO96/36620, WO97/10230, WO98/28270, WO98/28275 and the like. Thecompounds described in J. Med. Chem. 1994, 37, 2125 and WO93/15062 havevery high affinity for δ receptors. However, these compounds have notbeen used clinically, because their productions are difficult due tothree asymmetric centers, which are apparent from their chemicalformulas, and they have poor pharmacokinetics. Derivatives having astructure with no asymmetric center are reported in WO96/36620,WO97/10230, WO98/28270, WO98/28275 and the like. However, theiraffinities for the δ receptor are undesirably lowered compared to thecompounds described above. Thus, no compound has been reported which hasa structure with no asymmetric center and high affinity for the δreceptor.

[0005] Further, the piperidine ring structure including R⁴, R⁵ and R⁶ ofthe general formula (I) of the present invention is already known.However, no compound has been reported which has these partial structureand high affinity for the δ receptor.

DISCLOSURE OF THE INVENTION

[0006] An aim of the present invention is to provide a substance havingaffinity for the opioid δ receptor, in particular, to provide aneffective and selective opioid δ receptor ligands. A further aim is toprovide a medicament useful for preventive and/or therapeutic treatmentof central nerve system diseases and peripheral nerve system diseases.

[0007] In the specification, the term “opioid δ receptor ligand” means acompound having an ability to bind to an opioid δ receptor, andcomprehensively includes an agonist, antagonist, partial agonist, andinverse agonist for an opioid δ receptor.

[0008] In order to achieve the aim described above, the inventors of thepresent invention studied variety of compounds. As a result, they foundthat compounds represented by the following general formula (I) had highaffinity for the opioid δ receptor, and achieved the present invention.

[0009] The present invention thus provides compounds represented by thefollowing general formula (I):

[0010] [in the formula, X represents the following group (II), (III),(IV), (V), or (VI),

[0011] “A” represents a saturated or unsaturated 3- to 6-memberedcarbocyclic group or a saturated or unsaturated monocyclic heterocyclicgroup containing one or more hetero atoms,

[0012] “B” represents —CH₂—, —CHOH—, —(C═O)—, —CH₂CH₂—, or a singlebond,

[0013] “n” represents 0, 1 or 2,

[0014] R¹ represents a hydrogen atom, a halogen atom, a lower alkylgroup which may be substituted, a lower alkenyl group which may besubstituted, a lower alkoxy group which may be substituted, a hydroxygroup, a cyano group, an amino group, a N,N-di(lower alkyl)amino group,a N,N-di(substituted lower alkyl)amino group, a nitro group, a carbamoylgroup, a N,N-di(lower alkyl)carbamoyl group, a N,N-di(substituted loweralkyl)carbamoyl group, a carboxyl group, a lower alkoxycarbonyl groupwhich may be substituted or a lower alkylcarbonyl group which may besubstituted,

[0015] R², R³, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, and R¹⁴ eachindependently represent a hydrogen atom, a lower alkyl group which maybe substituted or a lower alkenyl group which may be substituted,

[0016] R⁴ represents a hydrogen atom, a lower alkyl group which may besubstituted, a lower alkenyl group which may be substituted, or a loweralkoxy group which may be substituted,

[0017] R⁵ represents a hydrogen atom, a halogen atom, a lower alkylgroup which may be substituted, a lower alkenyl group which may besubstituted, a lower alkoxy group which may be substituted, a hydroxygroup, a cyano group, an amino group, a N,N-di(lower alkyl)amino group,a N,N-di(substituted lower alkyl)amino group, a carbamoyl group, aN,N-di(lower alkyl)carbamoyl group, a N,N-di(substituted loweralkyl)carbamoyl group, a carboxyl group, a lower alkoxycarbonyl groupwhich may be substituted or a lower alkylcarbonyl group which may besubstituted,

[0018] R⁶ represents a saturated or unsaturated monocyclic or bicycliccarbocyclic group, a saturated or unsaturated monocyclic or bicyclicheterocyclic group containing one or more hetero atoms, or a N-(loweralkyl)carbonyl-N-(substituted or unsubstituted phenyl)amino group, and

[0019] R⁵ and R⁶, R⁷ and R⁸, R⁹ and R¹⁰, and R¹¹ and R¹² may bind toeach other to form a cyclic structure] or salts thereof.

[0020] Further, the present invention provides medicaments comprising asubstance consisting of the compounds represented by the general formula(I) and pharmacologically acceptable salts thereof. The preferredmedicaments consist of a pharmaceutical composition comprising thesubstance described above and an additive for pharmaceuticalpreparations. These medicaments are useful for preventive treatmentand/or therapeutic treatment of central nerve system diseases orperipheral nerve system diseases.

[0021] The present invention further provides an opioid δ receptorligand comprising a substance consisting of the compounds represented bythe general formula (I) and pharmacologically acceptable salts thereof.

[0022] The present invention still further provides use of substancesconsisting of the compounds represented by the general formula (I) andpharmacologically acceptable salts thereof for manufacture of themedicaments, and methods for preventive and/or therapeutic treatment ofcentral nerve system diseases or peripheral nerve system diseases, whichcomprises a step of administering a preventively or therapeuticallyeffective amount of a substance consisting of the compounds representedby the general formula (I) and pharmacologically acceptable saltsthereof to a mammal including human.

BEST MODE FOR CARRYING OUT THE INVENTION

[0023] The present invention will be explained in detail. The entiredisclosures of Japanese Patent Application No. 2000-470791 (filed onFeb. 18, 2000) are incorporated by reference in the disclosures of thespecification.

[0024] Novel compounds of the present invention will be explained inmore detail.

[0025] In the specification, a “lower alkyl group” or a “lower alkoxygroup” as a substituent, or a “lower alkyl group” or “lower alkoxygroup” constituting a part of a substituent means an alkyl or alkoxygroup in a straight or branched chain, cyclic form, or any combinationthereof having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms.Examples thereof include methyl, ethyl, n-propyl, isopropyl,cyclopropyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, cyclopentyl,n-hexyl, cyclohexyl, methoxy, ethoxy, n-propoxy, isopropoxy,cyclopropoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy and the like.Similarly, a “lower alkenyl group” as a substituent means a straight,branched, or cyclic alkenyl group having 2 to 6 carbon atoms, preferably2 to 4 carbon atoms, and examples thereof include vinyl group, allylgroup and the like. In a group containing an alkenyl moiety, the numberof double bonds contained in the alkenyl moiety is not particularlylimited, and a double bond contained in the alkenyl moiety may either bein Z- or E-configuration.

[0026] The term “halogen atom” means a fluorine atom, chlorine atom,bromine atom or iodine atom unless otherwise specifically mentioned.

[0027] The term “hetero atom” means a hetero atom such as an oxygenatom, nitrogen atom, or sulfur atom, preferably an oxygen atom, nitrogenatom, or sulfur atom. A “heterocyclic ring” may contain two or morehetero atoms as ring-constituting atoms. In such compounds, two or morehetero atoms may be the same or different. A heterocyclic group means aresidue of a heterocyclic ring obtained by removing one or more hydrogenatoms that bind to ring-constituting atoms.

[0028] In the formula (I), R⁷ and R⁸ in the group (II), R⁹ and R¹⁰ inthe group (III), and R¹¹ and R¹² in the group (IV), which groups arerepresented by X, may independently bind to each other to form a cyclicstructure. Examples of the ring include aziridine, azetidine,pyrrolidine, or piperidine. An unsaturated bond may exist in a part ofthese rings.

[0029] Further, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³ and R¹⁴ in the group(II), (III), (IV), (V) or (VI) represented by X preferably representindependently a hydrogen atom or a lower alkyl group, or R⁷ and R⁸preferably bind to each other to represent pyrrolidine or piperidine.The group represented by X is preferably the group (II).

[0030] The integer represented by “n” is preferably 0.

[0031] Examples of the carbocyclic ring or heterocyclic ring thatconstitutes the saturated or unsaturated 3- to 6-membered carbocyclicgroup or saturated or unsaturated monocyclic heterocyclic groupcontaining one or more hetero atoms represented by A include rings ofcyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclopropene,cyclobutene, cyclobutadiene, cyclopentene, cyclopentadiene, cyclohexene,cyclohexadiene, benzene, furan, pyrrole, thiophene, thiazole, oxazole,imidazole, isothiazole, isoxazole, pyrazole, triazole, pyridine,pyrimidine, pyrazine, pyridazine and the like. Preferred examplesinclude cyclohexane, benzene, and furan, and benzene is more preferred.Further, X or B adjacent to A can exist at any substitutable position.

[0032] Further, these 3- to 6-membered carbocyclic groups orheterocyclic groups may have one or more substituents, and examples ofthe substituents include a lower alkyl group such as methyl group, alower alkoxy group such as methoxy group, a lower alkenyl group such asallyl group, a halogen atom, a hydroxy group, a cyano group, an aminogroup, a N,N-di(lower alkyl)amino group, a N,N-di(substituted loweralkyl)amino group, a nitro group, a carbamoyl group, a N,N-di(loweralkyl)carbamoyl group such as N,N-dimethylcarbamoyl group, aN,N-di(substituted lower alkyl)carbamoyl group, a carboxyl group, alower alkoxycarbonyl group which may be substituted such as amethoxycarbonyl group, a lower alkylcarbonyl group which may besubstituted such as an acetyl group and the like. When the compoundshave two or more substituents, the substituents may be the same ordifferent. Positions of the substituents are not limited, and they canexist at any substitutable positions.

[0033] The group represented by “B” is preferably —CH₂—.

[0034] “n” is preferably 0.

[0035] R¹ is preferably a hydrogen atom or a lower alkoxy group whichmay be substituted.

[0036] R² and R³ preferably represent a hydrogen atom or a lower alkylgroup, most prefeably a hydrogen atom.

[0037] R⁴ is preferably a hydrogen atom or a lower alkyl group which maybe substituted, most preferably a hydrogen atom.

[0038] R⁵ is preferably a hydrogen atom or a lower alkylcarbonyl groupwhich may be substituted.

[0039] Examples of the carbocyclic ring that constitutes the saturatedor unsaturated monocyclic or bicyclic carbocyclic group represented byR⁶ include rings of cyclopentane, cyclohexane, benzene, indane,naphthalene and the like, and preferred are benzene, indane andnaphthalene.

[0040] Examples of the heterocyclic ring that constitutes the saturatedor unsaturated monocyclic or bicyclic heterocyclic group containing oneor more hetero atoms represented by R⁶ include rings of imidazole,benzofuran, indole, benzothiophene, benzothiazole, benzoxazole,benzimidazole, benzotriazole, benzisothiazole, benzisoxazole, quinoline,isoquinoline, quinazoline, pyridinoimidazole, benzoxazine and the like,and preferred examples are imidazole, benzofuran, indole, benzimidazole,benzotriazole, benzisothiazole, benzisoxazole, quinoline, isoquinoline,quinazoline and benzoxazine. More preferred R⁶ is the following group(VII):

[0041] [in the group,

represents a single bond or a double bond,

[0042] R¹⁵ represents a hydrogen atom, a lower alkyl group which may besubstituted, a lower alkenyl group which may be substituted, or an oxogroup, and R¹⁵ preferably represents a hydrogen atom, a lower alkylgroup which may be substituted with hydroxy group or an oxo group,

[0043] R¹⁶ represents a hydrogen atom, a halogen atom, a lower alkylgroup which may be substituted, a lower alkenyl group which may besubstituted, a lower alkoxy group which may be substituted, a hydroxygroup, a cyano group, an amino group, a N,N-di(lower alkyl)amino group,a N,N-di(substituted lower alkyl)amino group, a nitro group, a carbamoylgroup, a N,N-di(lower alkyl)carbamoyl group, a N,N-di(substituted loweralkyl)carbamoyl group, a carboxyl group, a lower alkoxycarbonyl groupwhich may be substituted or a lower alkylcarbonyl group which may besubstituted, and R¹⁶ preferably represents a hydrogen atom, a loweralkyl group or a lower alkoxy group].

[0044] An unsaturated bond as a part of the monocyclic or bicycliccarbocyclic group or monocyclic or bicyclic heterocyclic ring containingone or more hetero atoms represented by R⁶ may be hydrogenated to form asaturated bond, or may be substituted with oxygen atom to form a cyclicketone, cyclic amide (lactam), cyclic ester (lactone), or cyclic ureidestructure. The substituting position of the adjacent piperidine ring maybe an arbitrary substitutable position.

[0045] One or more hydrogen atoms on the saturated or unsaturatedmonocyclic or bicyclic carbocyclic group or saturated or unsaturatedmonocyclic or bicyclic heterocyclic ring containing one or more heteroatoms represented by R⁶ may be substituted. Examples of the substituentinclude a lower alkyl group such as methyl group, a lower alkoxy groupsuch as methoxy group, a lower alkenyl group such as allyl group, ahalogen atom, a hydroxy group, a cyano group, an amino group, aN,N-di(lower alkyl)amino group, a N,N-di(substituted lower alkyl)aminogroup, a nitro group, a carbamoyl group, a N,N-di(lower alkyl)carbamoylgroup such as N,N-dimethylcarbamoyl group, a N,N-di(substituted loweralkyl)carbamoyl group, carboxyl group, a lower alkoxycarbonyl groupwhich may be substituted such as methoxycarbonyl group, a loweralkylcarbonyl group which may be substituted such as an acetyl group, anoxo group, a benzyl group, a hydroxymethyl group and the like, andpreferred substituents are a lower alkyl group, a lower alkoxy group, ahalogen atom, an oxo group, a benzyl group, and a hydroxymethyl group.When two or more substituents are included, these may be the same ordifferent. The positions of the substituents are not limited, and theycan exist at any substitutable positions.

[0046] Further, an example of the compounds wherein R⁵ and R⁶ bind toeach other to form a cyclic structure include the compounds in which aspiro ring is formed. Specifically, examples include the followinggroups (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), and(XVII). Preferred groups are groups (VIII), (IX), (X), (XI), (XIII),(XVI), and (XVII), more preferred groups are groups (VIII) and (IX), andmost preferred group is group (VIII) (in the following chemicalformulas, a spiro ring is formed in each upper ring. In the formulas,each of two solid lines drawn from a ring represents a single bond thatbinds to the 3- or 5-position of the piperidine ring on which R⁵ and R⁶substitute):

[0047] [in the formula, R¹⁷ represents a hydrogen atom, a lower alkylgroup which may be substituted or a lower alkenyl group which may besubstituted, preferably a hydrogen atom, a lower alkyl group which maybe substituted with a phenyl or a N,N-di(lower alkyl)carbamoylphenyl,R¹⁸ represents a hydrogen atom, a halogen atom, a lower alkyl groupwhich may be substituted, a lower alkenyl group which may besubstituted, a lower alkoxy group which may be substituted, a hydroxygroup, a cyano group, an amino group, a N,N-di(lower alkyl)amino group,a N,N-di(substituted lower alkyl)amino group, a nitro group, a carbamoylgroup, a N,N-di(lower alkyl)carbamoyl group, a N,N-di(substituted loweralkyl)carbamoyl group, a carboxyl group, a lower alkoxycarbonyl groupwhich may be substituted or a lower alkylcarbonyl group which may besubstituted, preferably a hydrogen atom or a lower alkoxy group,

[0048] R¹⁹, R²¹, R²⁶ and R²⁸ independently represent a hydrogen atom, alower alkyl group which may be substituted or a lower alkenyl groupwhich may be substituted, preferably a hydrogen atom or a lower alkylgroup,

[0049] R²⁰, R²², R²³, R²⁴, R²⁵, R²⁷ and R²⁹ independently represent ahydrogen atom, a halogen atom, a lower alkyl group which may besubstituted, a lower alkenyl group which may be substituted, a loweralkoxy group which may be substituted, a hydroxy group, a cyano group,an amino group, a N,N-di(lower alkyl)amino group, a N,N-di(substitutedlower alkyl)amino group, a nitro group, a carbamoyl group, aN,N-di(lower alkyl)carbamoyl group, a N,N-di(substituted loweralkyl)carbamoyl group, a carboxyl group, a lower alkoxycarbonyl groupwhich may be substituted or a lower alkylcarbonyl group which may besubstituted, preferably a hydrogen atom].

[0050] The definition that a group represented by R¹, R², R³, R⁴, R⁵,R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰,R²¹, R²², R²³, R²⁴, R²⁵, R²⁶, R²⁷, R²⁸ or R²⁹ “may be substituted” meansthat the group may have any one or more of substituents. When the grouphas two or more substituents, they may be the same or different. Thepositions of the substituents are not limited, and they can exist at anysubstitutable positions. Kinds of the substituents are not limited.Examples thereof include a lower alkyl group such as methyl group, alower alkoxy group such as methoxy group, a lower alkenyl group such asallyl group, a halogen atom, a hydroxy group, a cyano group, an aminogroup, a N,N-di(lower alkyl)amino group, a N,N-di(substituted loweralkyl)amino group, a nitro group, a carbamoyl group, a N,N-di(loweralkyl)carbamoyl group such as N,N-dimethylcarbamoyl group, aN,N-di(substituted lower alkyl)carbamoyl group, a carboxyl group, alower alkoxycarbonyl group which may be substituted such asmethoxycarbonyl group, a lower alkylcarbonyl group which may besubstituted such as acetyl group and saturated or unsaturated 3- to6-membered carbocyclic group such as cyclopropyl, cyclopentyl,cyclohexyl, and phenyl (these carbocyclic groups may have one or moresubstituents, and examples of the substituents include a lower alkylgroup such as methyl group, a lower alkoxy group such as methoxy group,a lower alkenyl group such as allyl group, a halogen atom, a hydroxygroup, a cyano group, an amino group, a N,N-di(lower alkyl)amino group,a nitro group, a carbamoyl group, a N,N-di(lower alkyl)carbamoyl groupsuch as N,N-dimethylcarbamoyl group, a carboxyl group, a (loweralkoxy)carbonyl group such as methoxycarbonyl group, a (loweralkyl)carbonyl group such as acetyl group and the like), and a phenylgroup is preferred.

[0051] Further, examples of the substituents of the N,N-di(substitutedlower alkyl)amino group, N,N-di(substituted lower alkyl)carbamoyl group,lower alkoxycarbonyl group which may be substituted, and loweralkylcarbonyl group which may be substituted include, for example, alower alkoxy group, a lower alkenyl group, a halogen atom, a hydroxygroup, a cyano group, an amino group, a N,N-di(lower alkyl)amino group,a nitro group, a carbamoyl group, a N,N-di(lower alkyl)carbamoyl group,a carboxyl group, a lower alkoxycarbonyl group, and a loweralkylcarbonyl group.

[0052] Among the compounds represented by the general formula (I),examples of a preferred class of compounds include those wherein R⁶represents the following group (VII):

[0053] [in the group,

represents a single bond or a double bond, and R¹⁵ and R¹⁶ have the samemeanings as defined above].

[0054] Examples of another preferred class of compounds include thosewherein R⁵ and R⁶ form a cyclic structure and represent the followinggroup (VIII):

[0055] [in the group, R¹⁷ and R¹⁸ have the same meanings as definedabove].

[0056] More preferred class of the compounds include those wherein Xrepresents the group (II), (III), (V) or (VI),

[0057] “A” represents a residue of a ring selected from the groupconsisting of benzene, cyclohexane and furan,

[0058] “B” is —CH₂—, —CHOH—, —(C═O)—, —CH₂CH₂— or a single bond,

[0059] “n” is 0, 1 or 2,

[0060] R¹ is a hydrogen atom or a lower alkoxy group,

[0061] R², R³, R⁷, R⁸, R⁹, R¹⁰, R¹³ and R¹⁴ each independently representa hydrogen atom or a lower alkyl group which may be substituted,

[0062] R⁴ is a hydrogen atom or a lower alkyl group which may besubstituted,

[0063] R⁵ is a hydrogen atom or a lower alkylcarbonyl group which may besubstituted,

[0064] R⁶ is a residue of a ring selected from the group consisting ofbenzene, naphthalene, indane, benzofuran, imidazole, benzimidazole,indole, quinoline, benzotriazole, benzimidazole, benzisothiazole,benzisoxazole, quinazoline, isoquinoline and benzoxazine (a hydrogenatom on the ring may be replaced with halogen, oxo, lower alkyl,hydroxymethyl, lower alkoxy or benzyl), or R⁵ and R⁶ bind to each otherto form a residue of a ring selected from the group consisting ofindane, imidazole, N-phenylimidazolidine, isoquinoline, quinoline andbenzofuran (a hydrogen atom on the ring may be replaced with oxo, loweralkyl or lower alkoxy), and R⁷ and R⁸ bind to each other to formpyrrolidine or piperidine.

[0065] Examples of further preferred class of the compounds includethose wherein X represents the group (II).

[0066] In the present invention, among the compounds represented by thegeneral formula (I), particularly preferred compounds are as follows.

[0067] 1.1-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]-4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine

[0068] 2.1-[3-[2-(4-Diethylcarbamoylbenzyl)phenoxy]propyl]-4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine

[0069] 3.8-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one

[0070] 4.3-Benzyl-8-[2-[2-(4-diethylcarbamoylbenzyl)phenoxy]ethyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one

[0071] 5.3-Cyclopropylmethyl-8-[2-[2-(4-diethylcarbamoylbenzyl)phenoxy]ethyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one

[0072] 6.1-[4-[2-(4-Diethylcarbamoylbenzyl)phenoxy]butyl]-4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine

[0073] 7.8-[4-[2-(4-Diethylcarbamoylbenzyl)phenoxy]butyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one

[0074] 8.8-[3-[2-(4-Diethylcarbamoylbenzyl)phenoxy]propyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one

[0075] 9.4-(3-Benzyl-1,3-dihydro-2H-benzimidazol-2-on-1-yl)-1-[2-[2-(4-diethylcarbamoylbenzyl)phenoxy]ethyl]piperidine

[0076] 10.4-(3-Cyclopropylmethyl-1,3-dihydro-2H-benzimidazol-2-on-1-yl)-1-[2-[2-(4-diethylcarbamoylbenzyl)phenoxy]ethyl]piperidine

[0077] 11.1′-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]hexahydrospiro-[imidazo[1,2-a]pyridine-3(2H),4′-piperidin]-2-one

[0078] 12.1′-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]-5,6,7,8-tetrahydrospiro[imidazo[1,2-a]pyridine-3(2H),4′-piperidin]-2-one

[0079] 13.4-(1,3-Dihydro-2H-benzimidazol-2-on-1-yl)-1-[2-[2-(4-dimethylcarbamoylbenzyl)phenoxy]ethyl]piperidine

[0080] 14.8-[2-[2-(4-Dimethylcarbamoylbenzyl)phenoxy]ethyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one

[0081] 15.4-(1,3-Dihydro-2H-benzimidazol-2-on-1-yl)-1-[2-[2-(4-pyrrolidinocarbonylbenzyl)phenoxy]ethyl]piperidine

[0082] 16.1-Phenyl-8-[2-[2-(4-pyrrolidinocarbonylbenzyl)phenoxy]ethyl]-1,3,8-triazaspiro[4,5]decan-4-one

[0083] 17.1-[2-[3-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]-4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine

[0084] 18.8-[2-[3-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one

[0085] 19.1-[2-[4-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]-4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine

[0086] 20.8-[2-[4-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one

[0087] 21.4-(1,3-Dihydro-2H-benzimidazol-2-on-1-yl)-1-[2-[2-(4-piperidinocarbonylbenzyl)phenoxy]ethyl]piperidine

[0088] 22.1-Phenyl-8-[2-[2-(4-piperidinocarbonylbenzyl)phenoxy]ethyl]-1,3,8-triazaspiro[4,5]decan-4-one

[0089] 23.1-[2-[2-(4-Diethylcarbamoylbenzoyl)phenoxy]ethyl]-4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine

[0090] 24.8-[2-[2-(4-Diethylcarbamoylbenzoyl)phenoxy]ethyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one

[0091] 25.1-[2-[2-[1-(4-Diethylcarbamoylphenyl)-1-hydroxymethyl]phenoxy]ethyl]-4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine

[0092] 26.8-[2-[2-[1-(4-Diethylcarbamoylphenyl)-1-hydroxymethyl]phenoxy]ethyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one

[0093] 27.1-[2-[2-(3-Diethylcarbamoylbenzyl)phenoxy]ethyl]-4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine

[0094] 28.8-[2-[2-(3-Diethylcarbamoylbenzyl)phenoxy]ethyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one

[0095] 29.1-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]propyl]-4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine

[0096] 30.8-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]propyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one

[0097] 31.4-(1,3-Dihydro-2H-benzimidazol-2-on-1-yl)-1-[2-[2-(4-diisopropylcarbamoylbenzyl)phenoxy]ethyl]piperidine

[0098] 32.8-[2-[2-(4-Diisopropylcarbamoylbenzyl)phenoxy]ethyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one

[0099] 33.1-[2-[2-[2-(4-Diethylcarbamoylphenyl)ethyl]phenoxy]ethyl]-4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine

[0100] 34.8-[2-[2-[2-(4-Diethylcarbamoylphenyl)ethyl]phenoxy]ethyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one

[0101] 35.1-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]-4-(1,3-dihydro-3-methyl-2H-benzimidazol-2-on-1-yl)piperidine

[0102] 36.8-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]-3-methyl-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one

[0103] 37.1-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]-4-(2,3-dihydro-1H-indol-2-on-3-yl)piperidine

[0104] 38.1-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]-4-(1,2,3,4-tetrahydroquinolin-1-yl)piperidine

[0105] 39.1-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]-4-(1,2,3,4-tetrahydronaphthalen-1-yl)piperidine

[0106] 40.1-[2-[2-(4-Diethylcarbamoylphenyl)phenoxy]ethyl]-4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine

[0107] 41.8-[2-[2-(4-Diethylcarbamoylphenyl)phenoxy]ethyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one

[0108] 42.1-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]-4-(indan-1-yl)piperidine

[0109] 43.1-[2-[3-(4-Diethylcarbamoylphenyl)phenoxy]ethyl]-4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine

[0110] 44.8-[2-[3-(4-Diethylcarbamoylphenyl)phenoxy]ethyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one

[0111] 45.1-[2-[3-(3-Diethylcarbamoylphenyl)phenoxy]ethyl]-4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine

[0112] 46.8-[2-[3-(3-Diethylcarbamoylphenyl)phenoxy]ethyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one

[0113] 47.1-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]-4-(1H-benzimidazol-1-yl)piperidine

[0114] 48.1-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]-4-(1,2,3,4-tetrahydroquinolin-2-on-1-yl)piperidine

[0115] 49.4-Acetyl-1-[2-[2-(4-diethylcarbamoylbenzyl)phenoxy]ethyl]-4-phenylpiperidine

[0116] 50.1-[2-[2-(3-Diethylcarbamoylphenyl)phenoxy]ethyl]-4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine

[0117] 51.8-[2-[2-(3-Diethylcarbamoylphenyl)phenoxy]ethyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one

[0118] 52.1-[1-[2-(4-Diethylcarbamoylbenzyl)phenoxymethyl]ethyl]-4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine

[0119] 53.4-(1H-Benzotriazol-1-yl)-1-[2-[2-(4-diethylcarbamoylbenzyl)phenoxy]ethyl]-piperidine

[0120] 54.1-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]-4-(2,3-dihydro-1H-indol-1-yl)piperidine

[0121] 55.8-[1-[2-(4-Diethylcarbamoylbenzyl)phenoxymethyl]ethyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one

[0122] 56.4-(1H-Benzimidazol-1-yl)-1-[1-[2-(4-diethylcarbamoylbenzyl)phenoxymethyl]-ethyl]piperidine

[0123] 57.1-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]-4-(6-fluoro-1,2-benzisothiazol-3-yl)piperidine

[0124] 58.1-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine

[0125] 59.1-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]-4-(1H-indol-3-yl)piperidine

[0126] 60.1′-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]-2,3-dihydrospiro[1H-indene-1,4′-piperidine]

[0127] 61.(R)-1-[1-[2-(4-Diethylcarbamoylbenzyl)phenoxymethyl]ethyl]-4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine

[0128] 62.(S)-1-[1-[2-(4-Diethylcarbamoylbenzyl)phenoxymethyl]ethyl]-4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine

[0129] 63.1-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]-4-(1,2,3,4-tetrahydroquinazolin-2-on-1-yl)piperidine

[0130] 64.1′-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]-2,3-dihydrospiro[isoquinoline-4(1H),4′-piperidin]-1-one

[0131] 65.1-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]spiro[piperidine-4,4′(1′H)-quinolin]-2′(3′H)-one

[0132] 66.1′-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]spiro[1H-indene-1,4′-piperidin]-3(2H)-one

[0133] 67.1-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]-4-(3,3-dimethyl-2,3-dihydro-1H-indol-2-on-1-yl)piperidine

[0134] 68.1-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]-4-phenylpiperidine

[0135] 69.1-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]-4-(1H-indol-1-yl)piperidine

[0136] 70.1′-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]spiro[3H-indole-3,4′-piperidin]-2(1H)-one

[0137] 71.1′-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]spiro[1H-indene-1,4′-piperidine]

[0138] 72.1-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]-4-(2-methyl-1H-benzimidazol-1-yl)piperidine

[0139] 73.1-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]-4-(3,4-dihydro-2H-1,4-benzoxazin-3-on-4-yl)piperidine

[0140] 74.1-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]-4-(1H-imidazol-1-yl)piperidine

[0141] 75.1-[1-[2-(4-Diethylcarbamoylbenzyl)phenoxymethyl]propyl]-4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine

[0142] 76.8-[1-[2-(4-Diethylcarbamoylbenzyl)phenoxymethyl]propyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one

[0143] 77.1′-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]spiro[isobenzofuran-1(3H),4′-piperidin]-3-one

[0144] 78.1-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]-4-(6-fluoro-1H-indol-3-yl)piperidine

[0145] 79.1-[2-[2-(4-Diethylcarbamoylbenzyl)-4-methoxyphenoxy]ethyl]-4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine

[0146] 80.8-[2-[2-(4-Diethylcarbamoylbenzyl)-4-methoxyphenoxy]ethyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one

[0147] 81.1-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]-4-(1,3-dihydro-7-methyl-2H-benzimidazol-2-on-1-yl)piperidine

[0148] 82.1-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]-4-(5-fluoro-1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine

[0149] 83.1′-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]-2,3-dihydro-5-methylspiro[isoquinoline-4(1H),4′-piperidin]-1-one

[0150] 84.1-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]-4-(2-hydroxymethyl-1H-benzimidazol-1-yl)piperidine

[0151] 85.1-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]-4-[2-(2-hydroxyethyl)-1H-benzimidazol-1-yl]piperidine

[0152] 86.1-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]-4-(2-hydroxymethyl-7-methyl-1H-benzimidazol-1-yl)piperidine

[0153] 87.1-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]-4-(2-hydroxymethyl-7-methoxy-1H-benzimidazol-1-yl)piperidine

[0154] 88.1-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]-4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)-3-methylpiperidine

[0155] 89.1-[2-[2-(4-Diethylaminosulfonylbenzyl)phenoxy]ethyl]-4-(2-hydroxymethyl-1H-benzimidazol-1-yl)piperidine

[0156] 90.1-[2-[2-(4-Diethylaminosulfonylbenzyl)phenoxy]ethyl]-4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine

[0157] 91.8-[2-[2-(4-Diethylaminosulfonylbenzyl)phenoxy]ethyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one

[0158] 92.1-[2-[2-(3-Diethylaminosulfonylbenzyl)phenoxy]ethyl]-4-(2-hydroxymethyl-1H-benzimidazol-1-yl)piperidine

[0159] 93.1-[2-[2-(3-Diethylaminosulfonylbenzyl)phenoxy]ethyl]-4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine

[0160] 94.8-[2-[2-(3-Diethylaminosulfonylbenzyl)phenoxy]ethyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one

[0161] 95.1-[2-[2-[(5-Diethylcarbamoylfuran-2-yl)methyl]phenoxy]ethyl]-4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine

[0162] 96.8-[2-[2-[(5-Diethylcarbamoylfuran-2-yl)methyl]phenoxy]ethyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one

[0163] 97.1-[2-[2-[(5-Diethylcarbamoylfuran-2-yl)methyl]phenoxy]ethyl]-4-(2-hydroxymethyl-1H-benzimidazol-1-yl)piperidine

[0164] 98.1′-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]-2,3-dihydro-5-methoxyspiro[isoquinoline-4(1H),4′-piperidin]-1-one

[0165] 99.1-[2-[2-[(4-Diethylaminomethyl)benzyl]phenoxy]ethyl]-4-(2-hydroxymethyl-1H-benzimidazol-1-yl)piperidine

[0166] 100.1-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]-4-(2-hydroxymethyl-1H-benzimidazol-1-yl)-3-methylpiperidine

[0167] 101.1-[2-[2-(3-Diethylcarbamoylbenzyl)phenoxy]ethyl]-4-(2-hydroxymethyl-1H-benzimidazol-1-yl)piperidine

[0168] 102.1-[2-[2-(3-Diethylcarbamoylbenzyl)phenoxy]ethyl]-4-(2-hydroxymethyl-7-methyl-1H-benzimidazol-1-yl)piperidine

[0169] 103.1-[2-[2-(4-Isobutyloxycarbonylbenzyl)phenoxy]ethyl]-4-(2-hydroxymethyl-1H-benzimidazol-1-yl)piperidine

[0170] 104.1-[2-[2-(4-Isobutyloxycarbonylbenzyl)phenoxy]ethyl]-4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine

[0171] 105.8-[2-[2-(4-Isobutyloxycarbonylbenzyl)phenoxy]ethyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one

[0172] 106.1-[2-[2-(4-Carboxybenzyl)phenoxy]ethyl]-4-(2-hydroxymethyl-1H-benzimidazol-1-yl)piperidine

[0173] 107.1-[2-[2-[trans-(4-Diethylcarbamoylcyclohexyl)methyl]phenoxy]ethyl]-4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine

[0174] 108.8-[2-[2-[trans-(4-Diethylcarbamoylcyclohexyl)methyl]phenoxy]ethyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one

[0175] 109.1-[2-[2-[trans-(4-Diethylcarbamoylcyclohexyl)methyl]phenoxy]ethyl]-4-(2-hydroxymethyl-1H-benzimidazol-1-yl)piperidine

[0176] 110.4-(2-Hydroxymethyl-1H-benzimidazol-1-yl)-1-[2-[2-[4-(1-methylbutyryl)benzyl]phenoxy]ethyl]piperidine

[0177] 111.1-[2-[2-[cis-(4-Diethylcarbamoylcyclohexyl)methyl]phenoxy]ethyl]-4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine

[0178] 112.8-[2-[2-[cis-(4-Diethylcarbamoylcyclohexyl)methyl]phenoxy]ethyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one

[0179] 113.1-[2-[2-[cis-(4-Diethylcarbamoylcyclohexyl)methyl]phenoxy]ethyl]-4-(2-hydroxymethyl-1H-benzimidazol-1-yl)piperidine

[0180] 114.2-Benzyl-1′-[2-[2-(4-diethylcarbamoylbenzyl)phenoxy]ethyl]-2,3-dihydrospiro-[isoquinoline-4(1H),4′-piperidin]-1-one

[0181] 115.2-(4-Diethylcarbamoylbenzyl)-1′-[2-[2-(4-diethylcarbamoylbenzyl)phenoxy]ethyl]-2,3-dihydrospiro[isoquinoline-4(1H),4′-piperidin]-1-one

[0182] 116.2-Cyclopropylmethyl-1′-[2-[2-(4-diethylcarbamoylbenzyl)phenoxy]ethyl]-2,3-dihydrospiro[isoquinoline-4(1H),4′-piperidin]-1-one

[0183] 117.2-(3-Diethylcarbamoylbenzyl)-1′-[2-[2-(4-diethylcarbamoylbenzyl)phenoxy]ethyl]-2,3-dihydrospiro[isoquinoline-4(1H),4′-piperidin]-1-one

[0184] 118.4-(N-Acetylanilino)-1-[2-[2-(4-diethylcarbamoylbenzyl)phenoxy]ethyl]piperidine

[0185] Methods for preparing the novel compounds of the presentinvention will be explained in more detail. The novel compounds of thepresent invention can be produced by the methods described below.

[0186] [in the formula, X, A, B, R¹, R², R³, R⁴, R⁵, R⁶, and n have thesame meaning as those defined in the general formula (I), W represents ahalogen atom excluding a fluorine atom or represents a leaving groupsuch as p-toluenesulfonyloxy group, methanesulfonyloxy group ortrifluoromethanesulfonyloxy group].

[0187] The compounds (XVIII) can be prepared by the methods described inJ. Med. Chem. 1994, 37, 2125 and WO97/10230 with modification, and aspecific preparation method is described in Reference Example 1 whichfollows.

[0188] The compounds (XIX) can be obtained as a commercially availablereagent or can also be obtained in accordance with a known method or aknown method with modification.

[0189] The compounds (I) of the present invention can be obtained by areaction of a compound (XVIII) and a compound (XIX) in a solvent that isnot involved in the reaction (for example, dichloromethane,tetrahydrofuran, methyl ethyl ketone, N,N-dimethylformamide, dimethylsulfoxide etc.) in the presence of a base (e.g., pyridine,triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, potassiumcarbonate, sodium carbonate etc.) at a certain reaction temperature ofwhich lower limit is 20° C. and upper limit is 100° C., preferably lowerlimit is 20° C. and upper limit is 50° C., for a reaction time of whichlower limit is 2 hours and upper limit is 48 hours, preferably lowerlimit is 16 hours and upper limit is 24 hours.

[0190] Further, among the novel compounds of the present invention, thecompounds (XXI) wherein R³ is H can also be produced by the methoddescribed below.

[0191] [in the formula, X, A, B, R¹, R², R⁴, R⁵, R⁶, and n have the samemeanings as those defined in the general formula (I).]

[0192] In a manner to the preparation of the compounds (XVIII), thecompounds (XX) can be produced by the methods described in J. Med. Chem.1994, 37, 2125 and WO97/10230 with modification, and a specificpreparation method is described in Reference Example 2 below.

[0193] Among the compounds of the general formula (I) according to thepresent invention, the compounds (XXI) wherein R³ is H can be obtainedby a reaction of a compound (XX) and a compound (XIX) in a solvent thatis not involved in the reaction (e.g., dichloroethane, tetrahydrofuran,dimethyl sulfoxide and the like) in the presence of sodiumtriacetoxyborohydride and acetic acid at a reaction temperature of whichlower limit is 20° C. and upper limit is 50° C., preferably lower limitis 20° C. and upper limit is 30° C., for a reaction time of which lowerlimit is 2 hours and upper limit is 48 hours, preferably lower limit is5 hours and upper limit is 16 hours.

[0194] In the synthesis of the compounds of the present invention,purification of a target compound from a reaction mixture is performedby methods usually used in the filed of organic chemistry, for example,a method comprising distribution and extraction of a reaction mixturebetween water and an arbitrarily organic solvent that is immiscible withwater (e.g., benzene, toluene, ethyl acetate, butyl acetate, methylisobutyl ketone, chloroform, dichloromethane and the like), followed byconcentration, crystallization and the like. Further, as required, forexample, fractionation purification by column chromatography usingalumina, silica gel or the like may also be performed.

[0195] Typical methods for producing the compounds of the presentinvention are specifically explained in detail in the examples of thepresent specification. Therefore, those skilled in the art can prepareany compound falling within the scope of the general formula (I) basedon explanations of the general preparation methods described above andexamples described later by appropriately choosing starting compounds,reagents, reaction conditions and the like, and if necessary, applyingappropriate modifications or alterations to the methods disclosed in theexamples.

[0196] The compounds of the present invention may be in the form of asalt. The salt may be an acid addition salt such as salts with inorganicacids including hydrochloric acid, nitric acid, hydrobromic acid, andsulfuric acid, salts with aliphatic monocarboxylic acids, dicarboxylicacids, hydroxyalkanoic acids, hydroxydialkanoic acids, amino acids andthe like, or salts deriving from non-toxic organic acids such asaromatic acids, aliphatic acids, and aromatic sulfonic acid. Examples ofsuch acid addition salts include hydrochloride, hydrobromide, nitrate,sulfate, hydrogensulfate, hydrogenphosphate, dihydrogenphosphate,acetate, propionate, tartrate, oxalate, malonate, succinate, fumarate,maleate, mandelate, benzoate, phthalate, methanesulfonate,benzenesulfonate, toluenesulfonate, citrate, lactate, malate, glycolate,trifluoroacetate and the like.

[0197] As well as the compounds in free form or salts thereof, anyhydrates and solvates thereof also fall within the scope of the presentinvention. The types of solvents that form the solvates are notparticularly limited. Examples include solvents such as methanol,ethanol, acetone, and diethyl ether. However, the solvents are notlimited to these examples.

[0198] The compounds of the present invention may have one or moreasymmetric carbon atoms depending on the type of substituent, and any ofstereoisomers such as optically active isomers or diastereoisomers in apure form, any mixtures of the stereoisomers, racemates and the likealso fall within the scope of the present invention.

[0199] The compounds of the present invention are characterized to haveaffinity for opioid δ receptor. Therefore, the compounds of the presentinvention are useful for preventive and/or therapeutic treatment ofcentral nerve system diseases such as schizophrenia, depression,cerebral apoplexy, epilepsy, Alzheimer's disease, and Parkinson'sdisease and peripheral nerve system diseases such as pains, in which theopioid δ receptor is involved.

[0200] The medicaments provided by the present invention arecharacterized to comprise at least one kind of the compound representedby the general formula (I) or pharmacologically acceptable salt thereofas an active ingredient. The medicaments of the present invention can beadministered to human or animals other than human by any of oral orparenteral routes (for example, intravenous injection, intramuscularinjection, subcutaneous administration, rectal administration,percutaneous administration, intraspinal administration). As themedicaments of the present invention, the substances as activeingredients, per se, may be administered. It is generally preferable toprepare and administer a pharmaceutical composition, as a form suitablefor the administration route, by using one or more kinds of additivesfor pharmaceutical preparations.

[0201] Specifically, examples of orally available formulations includetablets, capsules, powders, granules, syrups and the like. Examples ofparenteral formulations include injections such as intravenous andintramuscular injections, formulations for rectal administration, oilysuppositories, aqueous suppositories and the like.

[0202] These various pharmaceutical preparations can be prepared byusing additives for pharmaceutical preparations which are ordinarilyused, for example, excipients, disintegrating agents, binders,lubricants and coloring agents.

[0203] Examples of the excipients include lactose, glucose, cornstarch,sorbit, crystalline cellulose and the like. Examples of thedisintegrating agents include starch, sodium alginate, gelatin powder,calcium carbonate, calcium citrate, dextrin and the like. Example of thebinders include dimethylcellulose, polyvinyl alcohol, polyvinyl ether,methylcellulose, ethylcellulose, gum arabic, gelatin,hydroxypropylcellulose, polyvinylpyrrolidone and the like. Examples ofthe lubricants include talc, magnesium stearate, polyethylene glycor,hydrogenated vegetable oil and the like. Further, the pharmaceuticalpreparations can be prepared with addition of a buffer, pH modifier,stabilizer or the like as required.

[0204] Although content of the compound of the present invention in thepharmaceutical composition may vary depending on types of formulations.Generally, its lower limit is about 0.1% by weight and upper limit is50% by weigh, preferably lower limit is 0.5% by weight and upper limitis 20% by weight based on the total composition. A dose mayappropriately be determined depending on each case in consideration ofthe age, body weight, sex, type of a disease, severity of symptoms of apatient and the like. Generally, its lower limit is 1 mg and upper limitis 1000 mg, preferably its lower limit is 1 mg and upper limit is 300mg, per day for an adult. The dose is administered once a day or severaltimes a day dividedly.

EXAMPLES

[0205] The present invention will be explained more specifically withreference to the following examples and test example. However, the scopeof the present invention is not limited to these examples.

Reference Example 11-Bromo-3-[2-(4-diethylcarbamoylbenzyl)phenoxy]propane

[0206] (a) 4-Diethylcarbamoylbenzyl Alcohol

[0207] 4-Hydroxymethylbenzoic acid (10.0 g) was dissolved inN,N-dimethylformamide (200 ml), added with 1-hydroxybenzotriazole (9.766g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(WSC.HCl, 13.855 g) and stirred at room temperature for 1 hour. Thereaction mixture was added with diethylamine (13.6 ml) and furtherstirred at room temperature for 1 hour. The reaction mixture was addedwith water (200 ml) and extracted twice with dichloromethane (200 ml).The organic layer was dried over anhydrous magnesium sulfate, and thenthe solvent was evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (elution solvent:hexane:ethyl acetate=1:2) to obtain 12.80 g of the title compound.Yield: 94%.

[0208]¹H-NMR (CDCl₃) δ (ppm); 1.09 (3H, br-s), 1.26 (3H, br-s), 3.25(2H, br-s), 3.53 (2H, br-s), 4.66 (2H, s), 7.30 (4H, s)

[0209] MS (TSP); m/z 208 (MH⁺)

[0210] (b) 4-Diethylcarbamoylbenzaldehyde

[0211] Oxalyl chloride (10.8 ml) was dissolved in dichloromethane (260ml), added with dimethyl sulfoxide (17.5 ml) at −78° C. under an argongas flow and stirred at the same temperature for 5 minutes. The reactionmixture was added with a solution of 4-diethylcarbamoylbenzyl alcohol(12.80 g) dissolved in dichloromethane (260 ml) at −78° C. and furtherstirred at the same temperature for 30 minutes. The reaction mixture wasadded with triethylamine (43.1 ml) at −78° C. and further stirred atroom temperature for 30 minutes. After the reaction mixture was addedwith water (500 ml) and the layers were separated, the aqueous layer wasextracted with dichloromethane (500 ml). The organic layer was driedover anhydrous magnesium sulfate, and then the solvent was evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (elution solvent: hexane:ethyl acetate=1:1) to obtain12.075 g of the title compound. Yield: 95%.

[0212]¹H-NMR (CDCl₃) δ (ppm); 1.11 (3H, t, J=7 Hz), 1.27 (3H, t, J=7Hz), 3.23 (2H, q, J=7 Hz), 3.56 (2H, q, J=7 Hz), 7.53 (2H, d, J=8 Hz),7.93 (2H, d, J=8 Hz), 10.05 (1H, s)

[0213] MS (EI); m/z 205 (M⁺)

[0214] (c) 1-(4-Diethylcarbamoylphenyl)-1-(2-methoxyphenyl)methylAlcohol

[0215] A solution of 2-bromoanisole (12.1 ml) dissolved intetrahydrofuran (200 ml) was added with magnesium (2.368 g) and stirredat 60° C. for 1 hour to prepare a Grignard reagent. This Grignardreagent was added with a solution of 4-diethylcarbamoylbenzaldehyde(10.0 g) dissolved in tetrahydrofuran (200 ml) with ice cooling andstirred at room temperature for 1 hour. The reaction mixture was addedwith saturated aqueous ammonium chloride (400 ml) with ice cooling toquench the reaction and then extracted twice with dichloromethane (400ml). The organic layer was dried over anhydrous magnesium sulfate, andthen the solvent was evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (elution solvent:hexane:ethyl acetate=1:1) to obtain 14.14 g of the title compound.Yield: 93%.

[0216]¹H-NMR (CDCl₃) δ (ppm); 1.10 (3H, br-s), 1.23 (3H, br-s), 3.18(1H, d, J=5 Hz), 3.26 (2H, br-s), 3.56 (2H, br-s), 3.81 (3H, s), 6.05(1H, d, J=5 Hz), 6.85-7.00 (2H, m), 7.20-7.45 (6H, m)

[0217] MS (TSP); m/z 314 (MH⁺)

[0218] (d) 2-(4-Diethylcarbamoylbenzyl)phenol

[0219] 1-(4-Diethylcarbamoylphenyl)-1-(2-methoxyphenyl)methyl alcohol(14.14 g) was dissolved in pyridine (280 ml), added with aceticanhydride (140 ml) with ice cooling and stirred at room temperature for15 hours. After the reaction mixture was added with methanol (140 ml)with ice cooling and stirred at room temperature for 10 minutes, thesolvent was evaporated under reduced pressure to obtain1-(4-diethylcarbamoylphenyl)-1-(2-methoxyphenyl)methyl acetate.

[0220] The obtained1-(4-diethylcarbamoylphenyl)-1-(2-methoxyphenyl)methyl acetate wasdissolved in methanol (280 ml), added with 10% palladium/carbon (7 g)and ammonium formate (28.44 g) under argon atmosphere and stirred at 60°C. for 2 hours. After insoluble matters were removed by filtration, thesolvent was evaporated under reduced pressure to obtain2-(4-diethylcarbamoylbenzyl)anisole.

[0221] The obtained 2-(4-diethylcarbamoylbenzyl)anisole was dissolved indichloromethane (280 ml), added with boron tribromide (25.0 g) andstirred at room temperature for 3 hours. After the reaction mixture wasslowly poured into ice (300 g) with ice cooling to quench the reactionand the layers were separated, the aqueous layer was extracted withdichloromethane (300 ml). The organic layer was dried over anhydrousmagnesium sulfate, and then the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(elution solvent: hexane:ethyl acetate=1:1) to obtain 10.15 g of thetitle compound. Yield: 79% (for the three steps).

[0222]¹H-NMR (CDCl₃) δ (ppm); 1.10 (3H, br-s), 1.23 (3H, br-s), 3.27(2H, br-s), 3.53 (2H, br-s), 3.94 (2H, s), 6.70-6.80 (2H, m), 7.00-7.10(2H, m), 7.15-7.30 (4H, m)

[0223] MS (TSP); m/z 284 (MH⁺)

[0224] (e) 1-Bromo-3-[2-(4-diethylcarbamoylbenzyl)phenoxy]propane

[0225] 2-(4-Diethylcarbamoylbenzyl)phenol (100 mg) was dissolved intetrahydrofuran (2 ml), added with sodium hydride (60%, in oil, 21 mg)and stirred at 60° C. for 1.5 hours. The reaction mixture was added with1,3-dibromopropane (0.18 ml) and stirred at the same temperature for 3hours. After the reaction mixture was added with water (10 ml) and thelayers were separated, the aqueous layer was extracted withdichloromethane (10 ml). The organic layer was dried over anhydrousmagnesium sulfate, and then the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(elution solvent: hexane:ethyl acetate=3:1) to obtain 99 mg of the titlecompound. Yield: 69%.

[0226]¹H-NMR (CDCl₃) δ (ppm); 1.12 (3H, br-s), 1.22 (3H, br-s), 2.25(2H, m), 3.27 (2H, br-s), 3.44 (2H, t, J=6 Hz), 3.52 (2H, br-s), 3.98(2H, s), 4.08 (2H, t, J=6 Hz), 6.84-7.29 (8H, m)

Reference Example 2 1-[2-(4-Diethylcarbamoylbenzyl)phenoxy]acetaldehyde

[0227] (a) 1-[2-(4-Diethylcarbamoylbenzyl)phenoxy]-2,3-dihydroxypropane

[0228] The 2-(4-diethylcarbamoylbenzyl)phenol (355 mg) obtained inReference Example 1(d) was dissolved in a mixed solution of dioxane (3.6ml) and water (3.6 ml), added with 1 N aqueous sodium hydroxide (63 μl)and glycidol (0.12 ml) and stirred at 90° C. for 18 hours. The reactionmixture was added with water (30 ml) and extracted twice withdichloromethane (30 ml). The organic layer was dried over anhydrousmagnesium sulfate, and then the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(elution solvent: ethyl acetate) to obtain 263 mg of the title compound.Yield: 59%.

[0229]¹H-NMR (CDCl₃) δ (ppm); 1.12 (3H, br-s), 1.24 (3H, br-s), 2.24(1H, d, J=5 Hz), 2.66 (1H, t, J=5 Hz), 3.20-3.40 (4H, m), 3.53 (2H,br-s), 3.75-3.95 (3H, m), 3.99 (2H, s), 6.83 (1H, d, J=8 Hz), 6.95 (1H,t, J=8 Hz), 7.15-7.30 (6H, m)

[0230] MS (TSP); m/z 358 (MH⁺)

[0231] (b) 1-[2-(4-Diethylcarbamoylbenzyl)phenoxy]acetaldehyde

[0232] 1-[2-(4-Diethylcarbamoylbenzyl)phenoxy]-2,3-dihydroxypropane (263mg) was dissolved in a mixed solution of dioxane (2.6 ml) and water (2.6ml), added with sodium periodate (362 mg) and stirred at roomtemperature for 1 hour. The reaction mixture was added with water (10ml) and extracted twice with dichloromethane (10 ml). The organic layerwas dried over anhydrous magnesium sulfate, and then the solvent wasevaporated under reduced pressure to obtain 239 mg of the titlecompound. Yield: 100%.

[0233]¹H-NMR (CDCl₃) δ (ppm); 1.11 (3H, br-s), 1.22 (3H, br-s), 3.27(2H, br-s), 3.53 (2H, br-s), 4.07 (2H, s), 4.53 (2H, s), 6.71 (1H, d,J=8 Hz), 6.97 (1H, t, J=8 Hz), 7.14-7.29 (6H, m), 9.77 (1H, s)

Reference Example 3 3-Benzyl-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-oneTrifluoroacetate

[0234] (a)8-(tert-Butoxycarbonyl)-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one

[0235] 1-Phenyl-1,3,8-triazaspiro[4,5]decan-4-one (2.00 g) was dissolvedin a mixed solution of dichloromethane (20 ml) and methanol (20 ml),added with di-tert-butyl dicarbonate (2.98 ml) and diisopropylethylamine(2.26 ml) and stirred at room temperature for 14 hours. The solvent wasevaporated under reduced pressure, and then the residue was added withwater (50 ml) and extracted twice with dichloromethane (50 ml). Theorganic layer was dried over anhydrous magnesium sulfate, and then thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (elution solvent: hexane:ethylacetate=1:1) to obtain 2.173 g of the title compound. Yield: 76%.

[0236]¹H-NMR (CDCl₃) δ (ppm); 1.51 (9H, s), 1.69 (2H, d, J=14 Hz), 2.56(2H, br-s), 3.54 (2H, br-s), 4.05 (2H, br-s), 4.76 (2H, s), 6.70-6.90(4H, m), 7.20-7.30 (2H, m)

[0237] MS (TSP); m/z 332 (MH⁺)

[0238] (b)3-Benzyl-8-(tert-butoxycarbonyl)-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one

[0239]8-(tert-Butoxycarbonyl)-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one(1.441 g) was dissolved in N,N-dimethylformamide (28 ml), added withsodium hydride (60%, in oil, 521 mg) and stirred at room temperature for1.5 hours. The reaction mixture was added with benzyl bromide (1.81 ml)with ice cooling and further stirred at room temperature for 1 hour. Thereaction mixture was added with water (50 ml) and extracted twice withdichloromethane (70 ml). The organic layer was dried over anhydrousmagnesium sulfate, and then the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(elution solvent: hexane:ethyl acetate=5:1 >4:1) to obtain 1.710 g ofthe title compound. Yield: 94%.

[0240]¹H-NMR (CDCl₃) δ (ppm); 1.51 (9H, s), 1.65 (2H, d, J=14 Hz), 2.58(2H, br-s), 3.62 (2H, br-s), 4.05 (2H, br-s), 4.56 (2H, s), 4.61 (2H,s), 6.67 (1H, d, J=7 Hz), 6.81 (1H, t, J=7 Hz), 7.15-7.40 (8H, m)

[0241] MS (EI); m/z 421 (M⁺)

[0242] (c) 3-Benzyl-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-oneTrifluoroacetate

[0243]3-Benzyl-8-(tert-butoxycarbonyl)-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one(1.671 g) was added with trifluoroacetic acid (32 ml) with ice coolingand stirred at the same temperature for 1 hour. The solvent wasevaporated under reduced pressure and then the residue was added withdiisopropyl ether (50 ml) to precipitate the product. The precipitateswas collected by filtration and dried to obtain 1.561 g of the titlecompound. Yield: 91%.

[0244]¹H-NMR (CDCl₃) δ (ppm); 1.86 (2H, d, J=14 Hz), 3.04 (2H, dt, J=5Hz, 14 Hz), 3.43 (2H, d, J=12 Hz), 3.96 (2H, q, J=12 Hz), 4.61 (2H, s),4.62 (2H, s), 6.80-6.90 (2H, m), 7.20-7.45 (8H, m)

[0245] MS (EI); m/z 321 (M⁺)

Reference Example 4 4-(1,2,3,4-Tetrahydroquinolin-1-yl)piperidineTrifluoroacetate

[0246] (a)1-(tert-Butoxycarbonyl)-4-(1,2,3,4-tetrahydroquinolin-1-yl)piperidine

[0247] 1-(tert-Butoxycarbonyl)-4-piperidone (800 mg) was dissolved indichloroethane (16 ml), added with 1,2,3,4-tetrahydroquinoline (0.50ml), sodium triacetoxyborohydride (1.7 g) and acetic acid (2.3 ml) andstirred at room temperature for 24 hours. The reaction mixture was addedwith saturated aqueous sodium hydrogencarbonate (20 ml) and extractedtwice with ethyl acetate (20 ml). The organic layer was dried overanhydrous magnesium sulfate, and then the solvent was evaporated underreduced pressure. The residue was purified by preparative thin layersilica gel column chromatography (developing solvent: hexane:ethylacetate=10:1) to obtain 90.6 mg of the title compound. Yield: 7%.

[0248]¹H-NMR (CDCl₃) δ (ppm); 1.48 (9H, s), 1.70 (4H, m), 1.90 (2H, m),2.73 (2H, t, J=7 Hz), 2.79 (2H, m), 3.16 (2H, t, J=7 Hz), 3.75 (1H, m),4.25 (2H, m), 6.57 (1H, t, J=8 Hz), 6.66 (1H, d, J=8 Hz), 6.96 (1H, d,J=8 Hz), 7.05 (1H, t, J=8 Hz)

[0249] (b) 4-(1,2,3,4-Tetrahydroquinolin-1-yl)piperidineTrifluoroacetate

[0250] The title compound was obtained in the same manner in ReferenceExample 3(c) from1-(tert-butoxycarbonyl)-4-(1,2,3,4-tetrahydroquinolin-1-yl)piperidine.Yield: 100%.

[0251]¹H-NMR (CDCl₃) δ (ppm); 1.65 (2H, m), 2.07 (2H, m), 2.17 (2H, m),2.95 (2H, t, J=7 Hz), 3.15 (2H, m), 3.52 (2H, t, J=7 Hz), 3.58 (2H, m),3.96 (1H, m), 7.25 (4H, m)

[0252] MS (TSP); m/z 217 (MH⁺)

Reference Example 5 1-[2-(4-Diethylcarbamoylphenyl)phenoxy]acetaldehyde

[0253] (a) 4-Diethylcarbamoyl-1-iodobenzene

[0254] The title compound was obtained in the same manner in ReferenceExample 1(a) from 4-iodobenzoic acid. Yield: 92%.

[0255]¹H-NMR (CDCl₃) δ (ppm); 1.11 (3H, br-s), 1.23 (3H, br-s), 3.24(2H, br-s), 3.52 (2H, br-s), 7.12 (2H, d, J=8 Hz), 7.74 (2H, d, J=8 Hz)

[0256] MS (FAB); m/z 304 (MH⁺)

[0257] (b) 2-(4-Diethylcarbamoylphenyl)anisole

[0258] A solution of 2-bromoanisole (0.25 ml) dissolved intetrahydrofuran (5 ml) was added with magnesium (48.6 mg) and stirred at60° C. for 1 hour to prepare a Grignard reagent. This solution wascooled to −78° C., added with a solution of tributyl borate (0.65 ml)dissolved in tetrahydrofuran (5 ml) and gradually warmed to roomtemperature with stirring for 20 hours. The reaction mixture was addedwith saturated aqueous ammonium chloride (10 ml) with ice cooling,stirred for 10 minutes and then extracted twice with ether (10 ml). Theorganic layer was dried over anhydrous magnesium sulfate, and then thesolvent was evaporated under reduced pressure to obtain(2-methoxyphenyl)boric acid.

[0259] 4-Diethylcarbamoyl-1-iodobenzene (100 mg) was dissolved indimethoxyethane (1 ml), added with tetrakis(triphenylphosphine)palladium(19.1 mg) under argon atmosphere, and stirred at room temperature for 10minutes. The reaction mixture was added with the solution of(2-methoxyphenyl)boric acid (100 mg) dissolved in toluene (0.5 ml)prepared above and a solution of sodium carbonate (105 mg) dissolved inwater (0.5 ml) and stirred at 90° C. for 5.5 hours. The reaction mixturewas added with water (2 ml) and extracted twice with dichloromethane (4ml). The organic layer was dried over anhydrous magnesium sulfate, andthen the solvent was evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (elution solvent:hexane:ethyl acetate=3:1) to obtain 81.9 mg of the title compound.Yield: 88%.

[0260]¹H-NMR (CDCl₃) δ (ppm); 1.23 (6H, br-s), 3.36 (2H, br-s), 3.56(2H, br-s), 3.82 (3H, s), 6.95-7.05 (2H, m), 7.32 (2H, d, J=8 Hz), 7.41(2H, d, J=8 Hz), 7.56 (2H, d, J=8 Hz)

[0261] MS (FAB); m/z 284 (MH⁺)

[0262] (c) 2-(4-Diethylcarbamoylphenyl)phenol

[0263] 2-(4-Diethylcarbamoylphenyl)anisole (250 mg) was dissolved indichloromethane (10 ml), added with boron tribromide (0.42 ml) andstirred at room temperature for 3 hours. After the reaction mixture wasslowly poured into ice (20 g) with ice cooling to quench the reactionand the layers were separated, the aqueous layer was extracted withdichloromethane (10 ml). The organic layer was dried over anhydrousmagnesium sulfate, and then the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(elution solvent: hexane:ethyl acetate=2:1→1:1) to obtain 231 mg of thetitle compound. Yield: 97%.

[0264]¹H-NMR (CDCl₃) δ (ppm); 1.18 (3H, br-s), 1.26 (3H, br-s), 3.34(2H, br-s), 3.57 (2H, br-s), 7.00 (2H, t, J=8 Hz), 7.26 (2H, m), 7.50(4H, m)

[0265] MS (TSP); m/z 270 (MH⁺)

[0266] (d) 1-[2-(4-Diethylcarbamoylphenyl)phenoxy]-2,3-dihydroxypropane

[0267] The title compound was obtained in the same manner in ReferenceExample 2(a) from 2-(4-diethylcarbamoylphenyl)phenol. Yield: 87%.

[0268]¹H-NMR (CDCl₃) δ (ppm); 1.17 (3H, br-s), 1.26 (3H, br-s), 3.32(2H, br-s), 3.50-3.75 (4H, m), 3.90-4.10 (3H, m), 6.95-7.10 (2H, m),7.35 (2H, m), 7.42 (2H, d, J=8 Hz), 7.51 (2H, d, J=8 Hz)

[0269] MS (TSP); m/z 344 (MH⁺)

[0270] (e) 1-[2-(4-Diethylcarbamoylphenyl)phenoxy]acetaldehyde

[0271] The title compound was obtained in the same manner in ReferenceExample 2 (b) from1-[2-(4-diethylcarbamoylphenyl)phenoxy]-2,3-dihydroxypropane. Yield:100%.

[0272]¹H-NMR (CDCl₃) δ (ppm); 1.17 (3H, br-s), 1.26 (3H, br-s), 3.34(2H, br-s), 3.57 (2H, br-s), 4.53 (2H, s), 6.95-7.10 (2H, m), 7.35-7.45(4H, m), 7.51 (2H, d, J=8 Hz), 9.77 (1H, s)

Reference Example 6 4-(1H-Benzimidazol-1-yl)piperidine Trifluoroacetate

[0273] (a) 1-(Tert-Butoxycarbonyl)-4-hydroxypiperidine

[0274] 4-Hydroxypiperidine hydrochloride (3 g) was dissolved in dioxane(30 ml), added with di-tert-butyl dicarbonate (5.2 g) and stirred atroom temperature for 10 minutes. The reaction mixture was added with 8%aqueous sodium hydrogencarbonate (60 ml) and further stirred for 3.5hours. Dioxane was evaporated under reduced pressure, and the aqueouslayer was extracted with ethyl acetate (60 ml). The organic layer wasdried over anhydrous magnesium sulfate, and then the solvent wasevaporated under reduced pressure. The residue was purified to obtain4.81 g of the title compound. Yield: 100%.

[0275]¹H-NMR (CDCl₃) δ (ppm); 1.46 (11H, m), 1.86 (2H, m), 3.04 (2H, m),3.85 (3H, m)

[0276] (b) 1-(Tert-Butoxycarbonyl)-4-(p-toluenesulfonyloxy)piperidine

[0277] 1-(tert-Butoxycarbonyl)-4-hydroxypiperidine (4.81 g) wasdissolved in pyridine (48 ml), added with p-toluenesulfonyl chloride(9.0 g) and triethylamine (6.7 ml) and stirred at room temperature for17 hours. The reaction mixture was added with cold water (500 ml) andstirred for 2 hours, and then the produced crystals were collected byfiltration. These crystals were purified by silica gel columnchromatography (elution solvent: hexane:ethyl acetate=3:1) to obtain6.49 g of the title compound. Yield: 76%.

[0278]¹H-NMR (CDCl₃) δ (ppm); 1.43 (9H, s), 1.59 (2H, m), 1.70 (2H, m),2.45 (3H, s), 3.25 (2H, m), 3.57 (2H, m), 4.67 (1H, m), 7.34 (2H, d, J=8Hz), 7.79 (2H, d, J=8 Hz)

[0279] (c) 1-(Tert-Butoxycarbonyl)-4-(1H-benzimidazol-1-yl)piperidine

[0280] 1H-Benzimidazole (300 mg) was dissolved in N,N-dimethylformamide(6 ml), added with sodium hydride (60%, in oil, 122 mg) and stirred atroom temperature for 1 hour. Subsequently, the reaction mixture wasadded with 1-(tert-butoxycarbonyl)-4-(p-toluenesulfonyloxy)piperidine(1.08 g) and further stirred at room temperature for 23 hours and at 60°C. for 2 hours. The reaction mixture was added with water (10 ml) andextracted twice with ethyl acetate (10 ml). The organic layer was driedover anhydrous magnesium sulfate, and then the solvent was evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (elution solvent: ethyl acetate) to obtain 192 mg of thetitle compound. Yield: 25%.

[0281]¹H-NMR (CDCl₃) δ (ppm); 1.51 (9H, s), 2.03 (2H, m), 2.18 (2H, m),2.94 (2H, m), 4.36 (3H, m), 7.30 (2H, m), 7.43 (1H, m), 7.82 (1H, m),7.98 (1H, s)

[0282] MS (TSP); m/z 302 (MH⁺)

[0283] (d) 4-(1H-Benzimidazol-1-yl)piperidine Trifluoroacetate

[0284] The title compound was obtained in the same manner in ReferenceExample 3(c) from1-(tert-butoxycarbonyl)-4-(1H-benzimidazol-1-yl)piperidine. Yield: 100%.

[0285]¹H-NMR (D₂O) δ (ppm); 2.25 (2H, m), 2.48 (2H, m), 3.22 (2H, m),3.59 (2H, m), 4.96 (1H, m), 7.54 (2H, m), 7.72 (1H, m), 7.80 (1H, m),9.21 (1H, s)

Reference Example 7 4-(1,2,3,4-Tetrahydroquinazolin-2-on-1-yl)piperidineTrifluoroacetate

[0286] (a)1-(Tert-Butoxycarbonyl)-4-[(2-hydroxymethylphenyl)amino]piperidine

[0287] The title compound was obtained in the same manner in ReferenceExample 4(a) from 2-aminobenzyl alcohol and1-(tert-butoxycarbonyl)-4-piperidone. Yield: 68%.

[0288]¹H-NMR (CDCl₃) δ (ppm); 1.47 (2H, m), 1.50 (9H, s), 2.01 (2H, m),3.00 (2H, m), 3.50 (1H, m), 3.99 (2H, m), 4.67 (2H, s), 6.66 (2H, m),7.05 (1H, d, J=8 Hz), 7.21 (1H, t, J=8 Hz)

[0289] (b)1-(Tert-Butoxycarbonyl)-4-(1,2,3,4-tetrahydroquinazolin-2-on-1-yl)piperidine

[0290]1-(tert-Butoxycarbonyl)-4-[(2-hydroxymethylphenyl)amino]piperidine (716mg) was dissolved in tetrahydrofuran (7 ml), added with phthalimide (349mg), triphenylphosphine (736 mg) and diethyl azodicarboxylate (0.43 ml)and stirred at room temperature for 21 hours. The reaction mixture wasadded with water (10 ml) and extracted twice with dichloromethane (10ml). The organic layer was dried over anhydrous magnesium sulfate, andthen the solvent was evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (elution solvent:hexane:ethyl acetate=4:1) to obtain crude1-(tert-butoxycarbonyl)-4-[(2-phthalimidylmethylphenyl)amino]piperidine(420 mg).

[0291] Subsequently, the resulting crude1-(tert-butoxycarbonyl)-4-[(2-phthalimidylmethylphenyl)amino]piperidine(420 mg) was dissolved in ethanol (8 ml), added with hydrazinemonohydrate (0.23 ml) and stirred at room temperature for 1 hour and at40° C. for 1 hour. After insoluble matters were removed by filtrationfrom the reaction mixture, the solvent was evaporated under reducedpressure. The residue was added with water (10 ml) and extracted twicewith dichloromethane (10 ml). The solvent was evaporated under reducedpressure to obtain 219 mg of1-(tert-butoxycarbonyl)-4-[(2-aminomethylphenyl)amino]piperidine.

[0292] The obtained1-(tert-butoxycarbonyl)-4-[(2-aminomethylphenyl)amino]-piperidine (219mg) was dissolved in toluene (5 ml), added with 1,1′-carbonyldiimidazole(128 mg) and stirred at 100° C. for 1.5 hours. The reaction mixture wasadded with water (10 ml) and extracted twice with ethyl acetate (10 ml).The organic layer was dried over anhydrous magnesium sulfate, and thenthe solvent was evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (elution solvent:hexane:ethyl acetate=1:2→1:3) to obtain 130 mg of the title compound.Yield: 17% (for the three steps).

[0293]¹H-NMR (CDCl₃) δ (ppm); 1.49 (11H, m), 1.79 (2H, m), 2.60 (2H, m),2.80 (2H, m), 4.14 (1H, m), 4.24 (2H, s), 5.24 (1H, br-s), 7.04 (3H, m),7.24 (1H, m)

[0294] MS (TSP); m/z 332 (MH⁺)

[0295] (c) 4-(1,2,3,4-Tetrahydroquinazolin-2-on-1-yl)piperidineTrifluoroacetate

[0296] The title compound was obtained in the same manner in ReferenceExample 3(c) from1-(tert-butoxycarbonyl)-4-(1,2,3,4-tetrahydroquinazolin-2-on-1-yl)piperidine.Yield: 100%.

[0297]¹H-NMR (DMSO-d₆) δ (ppm); 1.86 (2H, m), 2.79 (2H, m), 3.06 (2H,m), 3.35 (2H, m), 4.11 (3H, m), 6.97 (1H, t, J=8 Hz), 7.17 (2H, d, J=8Hz), 7.24 (1H, d, J=8 Hz)

[0298] MS (FAB); m/z 232 (MH⁺)

Reference Example 8 4-Phenylpiperidine Hydrochloride

[0299] 1,2,3,6-Tetrahydro-4-phenylpyridine hydrochloride (70 mg) wasdissolved in methanol (1.4 ml), added with 10% palladium/carbon (35 mg)and stirred at 45° C. for 5 hours under hydrogen gas atmosphere. Afterinsoluble matters were removed by filtration, the solvent was evaporatedunder reduced pressure to obtain 70.0 mg of the title compound. Yield:99%.

[0300]¹H-NMR(CD₃OD) δ (ppm); 1.93 (2H, m), 2.06 (2H, m), 2.89 (1H, m),3.13 (2H, m), 3.49 (2H, m), 7.20-7.34 (5H, m)

[0301] MS (EI); m/z 161 (M⁺)

Reference Example 9 Spiro[3H-indole-3,4′-piperidin]-2(1H)-oneHydrochloride

[0302] (a)3-[2-[N-Benzyl-N-(2-hydroxyethyl)amino]ethyl]-2,3-dihydro-1H-indol-2-one

[0303] The title compound was obtained in the same manner in ReferenceExample 4(a) from N-benzylethanolamine and3-formylmethyl-2,3-dihydro-1H-indol-2-one synthesized in accordance withthe descriptions of WO98/08816. Yield: 79%.

[0304]¹H-NMR (CDCl₃) δ (ppm); 2.19 (2H, m), 2.50-2.80 (4H, m), 2.97 (1H,br-s), 3.50-3.65 (5H, m), 6.80-7.05 (3H, m), 7.10-7.30 (6H, m), 8.98(1H, s)

[0305] MS (EI); m/z 310 (M⁺)

[0306] (b)3-[2-[N-(Benzyloxycarbonyl)-N-(2-hydroxyethyl)amino]ethyl]-2,3-dihydro-1H-indol-2-one

[0307]3-[2-[N-Benzyl-N-(2-hydroxyethyl)amino]ethyl]-2,3-dihydro-1H-indol-2-one(463 mg) was dissolved in dichloromethane (9.2 ml), added with benzylchloroformate (0.51 ml) and potassium hydrogencarbonate (358 mg) andstirred at room temperature for 24 hours. The reaction mixture was addedwith water (10 ml) and extracted twice with dichloromethane (10 ml). Theorganic layer was dried over anhydrous magnesium sulfate, and then thesolvent was evaporated under reduced pressure. The residue was dissolvedin methanol (10 ml), added with 1 N aqueous sodium hydroxide (2.2 ml)and stirred for 30 minutes. The reaction mixture was added with water(50 ml) and extracted twice with dichloromethane (40 ml). The organiclayer was dried over anhydrous magnesium sulfate, and then the solventwas evaporated under reduced pressure. The residue was purified bysilica gel column chromatography (elution solvent: ethyl acetate) toobtain 272 mg of the title compound. Yield: 52%.

[0308]¹H-NMR (CDCl₃) δ (ppm); 2.25 (2H, m), 2, 85 (1H, m), 3.49 (4H, m),3.77 (2H, m), 5.05 (1H, d, J=12 Hz), 5.12 (1H, d, J=12 Hz), 6.81 (1H, d,J=8 Hz), 6.90-7.10 (2H, m), 7.19 (1H, t, J=8 Hz), 7.34 (5H, m),7.60-7.80 (1H, m)

[0309] MS (TSP); m/z 355 (MH⁺)

[0310] (c)3-[2-[N-(Benzyloxycarbonyl)-N-(2-methanesulfonyloxyethyl)amino]ethyl]-2,3-dihydro-1H-indol-2-one

[0311]3-[2-[N-(Benzyloxycarbonyl)-N-(2-hydroxyethyl)amino]ethyl]-2,3-dihydro-1H-indol-2-one (256 mg) was dissolved in dichloromethane (5 ml), added withtriethylamine (0.20 ml) and methanesulfonyl chloride (0.11 ml) with icecooling and stirred at room temperature for 1.5 hours. The reactionmixture was added with water (5 ml) and extracted twice withdichloromethane (5 ml). The organic layer was dried over anhydrousmagnesium sulfate, and then the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(elution solvent: hexane:ethyl acetate=1:2) to obtain 158 mg of thetitle compound. Yield: 51%.

[0312]¹H-NMR (CDCl₃) δ (ppm); 2.23 (2H, m), 2.85-3.00 (3H, m), 3.30-3.70(5H, m), 4.20-4.40 (2H, m), 5.07 (1H, d, J=12 Hz), 5.14 (1H, d, J=12Hz), 6.85 (1H, d, J=8 Hz), 6.92 (1H, m), 7.13 (1H, m), 7.20 (1H, t, J=8Hz), 7.35 (5H, m), 7.80-7.95 (1H, m)

[0313] MS (FAB); m/z 433 (MH⁺)

[0314] (d)1′-(Benzyloxycarbonyl)spiro[3H-indole-3,4′-piperidin]-2(1H)-one

[0315]3-[2-[N-(Benzyloxycarbonyl)-N-(2-methanesulfonyloxyethyl)amino]ethyl]-2,3-dihydro-1H-indol-2-one(158 mg) was dissolved in N,N-dimethylformamide (3 ml), added withsodium hydride (60%, in oil, 29.2 mg) and stirred at room temperaturefor 1.5 hours. The reaction mixture was added with water (10 ml) andextracted twice with dichloromethane (10 ml). The organic layer wasdried over anhydrous magnesium sulfate, and then the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (elution solvent: hexane:ethyl acetate=2:1) toobtain 74.6 mg of the title compound. Yield: 61%.

[0316]¹H-NMR (CDCl₃) δ (ppm); 1.58 (4H, m), 3.90 (4H, m), 5.19 (2H, s),6.89 (1H, d, J=8 Hz), 7.05 (1H, t, J=8 Hz), 7.23 (1H, t, J=8 Hz),7.30-7.40 (6H, m), 7.56 (1H, s)

[0317] MS (FAB); m/z 337 (MH⁺)

[0318] (e) Spiro[3H-indole-3,4′-piperidin]-2(1H)-one Hydrochloride

[0319] 1′-(Benzyloxycarbonyl)spiro[3H-indole-3,4′-piperidine]-2(1H)-one(74.6 mg) was dissolved in methanol (1.5 ml), added with 10%palladium/carbon (14 mg) and stirred at room temperature for 4 hoursunder hydrogen gas atmosphere. After insoluble matters were removed byfiltration, the reaction mixture was added with 1 N aqueous hydrochloricacid (0.33 ml), and the solvent was evaporated under reduced pressure toobtain 51.7 mg of the title compound. Yield: 98%.

[0320]¹H-NMR (D₂O) δ (ppm); 2.11 (4H, m), 3.48 (2H, m), 3.72 (2H, m),7.07 (1H, d, J=8 Hz), 7.18 (1H, t, J=8 Hz), 7.35 (1H, t, J=8 Hz), 7.45(1H, d, J=8 Hz)

[0321] MS (TSP); m/z 203 (MH⁺)

Reference Example 104-(3,4-Dihydro-2H-1,4-benzoxazin-3-on-4-yl)piperidine Trifluoroacetate

[0322] (a) 1-(Tert-Butoxycarbonyl)-4-[(2-hydroxyphenyl)amino]piperidine

[0323] The title compound was obtained in the same manner in ReferenceExample 4(a) from 1-(tert-butoxycarbonyl)-4-piperidone and2-aminophenol. Yield: 100%.

[0324]¹H-NMR (CDCl₃) δ (ppm); 1.37 (2H, m), 1.47 (9H, s), 2.00 (2H, m),2.91 (2H, m), 3.36 (1H, m), 4.04 (2H, m), 6.66 (1H, t, J=8 Hz), 6.74(2H, m), 6.83 (1H, t, J=8 Hz)

[0325] (b)1-(Tert-Butoxycarbonyl)-4-[(2-methoxycarbonylmethoxyphenyl)amino]piperidine

[0326] 1-(tert-Butoxycarbonyl)-4-[(2-hydroxyphenyl)amino]piperidine (50mg) was dissolved in N,N-dimethylformamide (1 ml), added with methylbromoacetate (17 μl) and potassium carbonate (25 mg) and stirred at roomtemperature for 17 hours. The reaction mixture was added with water (3ml) and extracted twice with ethyl acetate (3 ml). The organic layer wasdried over anhydrous magnesium sulfate, and then the solvent wasevaporated under reduced pressure. The residue was purified bypreparative thin layer silica gel column chromatography (developingsolvent: hexane:ethyl acetate=1:1) to obtain 51.8 mg of the titlecompound. Yield: 83%.

[0327]¹H-NMR (CDCl₃) δ (ppm); 1.44 (2H, m), 1.47 (9H, s), 2.04 (2H, m),2.97 (2H, m), 3.44 (1H, m), 3.80 (3H, s), 4.02 (2H, m), 4.64 (2H, s),6.63 (2H, m), 6.71 (1H, d, J=8 Hz), 6.91 (1H, t, J=8 Hz)

[0328] MS (TSP); m/z 365 (MH⁺)

[0329] (c)1-(Tert-Butoxycarbonyl)-4-[(2-carboxymethoxyphenyl)amino]piperidine

[0330]1-(tert-Butoxycarbonyl)-4-[(2-methoxycarbonylmethoxyphenyl)amino]piperidine (100 mg) was dissolved in methanol (1 ml), added with 1 N aqueoussodium hydroxide (0.55 ml) and stirred at room temperature for 1 hour.The reaction mixture was neutralized with 1 N aqueous hydrochloric acidand extracted twice with ethyl acetate (3 ml). The organic layer wasdried over anhydrous magnesium sulfate, and then the solvent wasevaporated under reduced pressure to obtain 72.1 mg of the titlecompound. Yield: 75%.

[0331]¹H-NMR (CDCl₃) δ (ppm); 1.46 (9H, s), 1.50 (2H, m), 1.97 (2H, m),2.84 (2H, m), 3.42 (1H, m), 4.05 (2H, m), 4.62 (2H, s), 6.95 (4H, m)

[0332] (d)1-(Tert-Butoxycarbonyl)-4-(3,4-dihydro-2H-1,4-benzoxazin-3-on-4-yl)piperidine

[0333]1-(tert-Butoxycarbonyl)-4-[(2-carboxymethoxyphenyl)amino]piperidine (351mg) was dissolved in dichloroethane (7 ml), added with thionyl chloride(73 μl) and stirred at room temperature for 1.5 hours. The reactionmixture was added with triethylamine (0.28 ml) and further stirred at40° C. for 2 hours. The reaction mixture was added with water (10 ml)and extracted twice with ethyl acetate (10 ml). The organic layer wasdried over anhydrous magnesium sulfate, and then the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (elution solvent: hexane:ethyl acetate=2:1) toobtain 191 mg of the title compound. Yield: 57%.

[0334]¹H-NMR (CDCl₃) δ (ppm); 1.49 (9H, s), 1.76 (2H, m), 2.54 (2H, m),2.80 (2H, m), 4.31 (2H, m), 4.40 (1H, m), 4.50 (2H, s), 7.02 (3H, m),7.13 (1H, m)

[0335] MS (TSP); m/z 333 (MH⁺)

[0336] (e) 4-(3,4-Dihydro-2H-1,4-benzoxazin-3-on-4-yl)piperidineTrifluoroacetate

[0337] The title compound was obtained in the same manner in ReferenceExample 3(c) from1-(tert-butoxycarbonyl)-4-(3,4-dihydro-2H-1,4-benzoxazin-3-on-4-yl)piperidine.Yield: 73%.

[0338]¹H-NMR (DMSO-d₆) δ (ppm); 1.89 (2H, m), 2.74 (2H, m), 3.06 (2H,m), 3.38 (2H, m), 4.33 (1H, m), 4.58 (2H, s), 7.06 (3H, m), 7.42 (1H, d,J=8 Hz)

Reference Example 114-(1.3-Dihydro-7-methyl-2H-benzimidazol-2-on-1-yl)piperidineHydrobromate

[0339] (a) 1-Benzyl-4-[(2-methyl-6-nitrophenyl)amino]piperidine

[0340] 4-Amino-1-benzylpiperidine (0.20 ml) was dissolved in dimethylsulfoxide (0.2 ml), added with 2-chloro-3-nitrotoluene (0.13 ml) andstirred at 100° C. for 19 hours. The reaction mixture was added withwater (2 ml) and extracted twice with ethyl acetate (2 ml). The organiclayer was dried over anhydrous magnesium sulfate, and then the solventwas evaporated under reduced pressure. The residue was purified bysilica gel column chromatography (elution solvent: hexane:ethylacetate=3:1) to obtain 51.1 mg of the title compound. Yield: 16%.

[0341]¹H-NMR (CDCl₃) δ (ppm); 1.51 (2H, m), 1.85 (2H, m), 2.07 (2H, m),2.35 (3H, s), 2.77 (2H, m), 3.28 (1H, m), 3.48 (2H, s), 6.82 (1H, t, J=8Hz), 7.22-7.31 (6H, m), 7.90 (1H, d, J=8 Hz)

[0342] MS (TSP, negative); m/z 325 (M⁻)

[0343] (b) 1-Ethoxycarbonyl-4-[(2-methyl-6-nitrophenyl)amino]piperidine

[0344] 1-Benzyl-4-[(2-methyl-6-nitrophenyl)amino]piperidine (45.2 mg)was dissolved in dichloromethane (0.9 ml), added with ethylchloroformate (27 μl) and potassium hydrogencarbonate (28 mg) andstirred at room temperature for 30 minutes. The reaction mixture wasadded with water (2 ml) and extracted twice with ethyl acetate (2 ml).The organic layer was dried over anhydrous magnesium sulfate, and thenthe solvent was evaporated under reduced pressure. The residue waspurified by preparative thin layer silica gel column chromatography(developing solvent: hexane:ethyl acetate=2:1) to obtain 38.3 mg of thetitle compound. Yield: 90%.

[0345]¹H-NMR (CDCl₃) δ (ppm); 1.25 (3H, t, J=7 Hz), 1.38 (2H, m), 1.87(2H, m), 2.38 (3H, s), 2.87 (2H, m), 3.37 (1H, m), 4.04 (2H, m), 4.13(2H, q, J=7 Hz), 6.54 (1H, d, J=9 Hz), 6.88 (1H, t, J=8 Hz), 7.35 (1H,d, J=8 Hz), 7.91 (1H, d, J=8 Hz)

[0346] (c) 4-[(2-Amino-6-methylphenyl)amino]-1-ethoxycarbonylpiperidine

[0347] 1-Ethoxycarbonyl-4-[(2-methyl-6-nitrophenyl)amino]piperidine (38mg) was dissolved in tetrahydrofuran (0.4 ml), added with a suspensionof Raney nickel in ethanol (0.2 ml) and stirred at 40° C. for 2 hoursunder hydrogen gas atmosphere. After insoluble matters were removed, thesolvent was evaporated under reduced pressure. The residue was purifiedby preparative thin layer silica gel column chromatography (developingsolvent: hexane:ethyl acetate=2:1) to obtain (28.6 mg) of the titlecompound. Yield: 83%.

[0348]¹H-NMR (CDCl₃) δ (ppm); 1.26 (3H, t, J=7 Hz), 1.35 (2H, m), 1.90(2H, m), 2.22 (3H, s), 2.76 (2H, m), 3.13 (1H, m), 4.12 (2H, q, J=7 Hz),4.18 (2H, m), 6.60 (2H, m), 6.80 (1H, t, J=8 Hz)

[0349] MS (FAB); m/z 277 (MH⁺)

[0350] (d)1-Ethoxycarbonyl-4-(1,3-dihydro-7-methyl-2H-benzimidazol-2-on-1-yl)piperidine

[0351] 4-[(2-Amino-6-methylphenyl)amino]-1-ethoxycarbonylpiperidine(75.2 mg) was dissolved in dichloromethane (1.5 ml), added withtriphosgene (80.5 mg) and triethylamine (76 μl) and stirred at roomtemperature for 2 hours. The reaction mixture was added with water (5ml) and extracted twice with ethyl acetate (5 ml). The organic layer wasdried over anhydrous magnesium sulfate, and then the solvent wasevaporated under reduced pressure. The residue was purified bypreparative thin layer silica gel column chromatography (developingsolvent: hexane:ethyl acetate=1:1) to obtain 59.1 mg of the titlecompound. Yield: 72%.

[0352]¹H-NMR (CDCl₃) δ (ppm); 1.29 (3H, t, J=7 Hz), 1.84 (2H, m), 2.60(3H, s), 2.78 (4H, m), 4.17 (2H, q, J=7 Hz), 4.38 (2H, m), 4.52 (1H, m),6.81 (1H, t, J=5 Hz), 6.95 (2H, d, J=5 Hz)

[0353] MS (TSP); m/z 304 (MH⁺)

[0354] (e) 4-(1,3-Dihydro-7-methyl-2H-benzimidazol-2-on-1-yl)piperidineHydrobromide

[0355]1-Ethoxycarbonyl-4-(1,3-dihydro-7-methyl-2H-benzimidazol-2-on-1-yl)piperidine(59 mg) was dissolved in 48% hydrobromic acid (0.3 ml) and stirred at100° C. for 1 hour. The reaction mixture was added with ethanol, and theproduced crystals were collected by filtration to obtain 26.8 mg of thetitle compound. Yield: 44%.

[0356]¹H-NMR (DMSO-d₆) δ (ppm); 1.95 (2H, m), 2.56 (3H, s), 2.80 (2H,m), 3.07 (2H, m), 3.38 (2H, m), 4.59 (1H, m), 6.75 (1H, d, J=8 Hz), 6.81(1H, d, J=8 Hz), 6.87 (1H, t, J=8 Hz)

[0357] MS (TSP); m/z 232 (MH⁺)

Reference Example 122,3-Dihydro-5-methylspiro[isoquinoline-4(1H),4′-piperidin]-1-oneTrifluoroacetate

[0358] (a) Bis(2-hydroxyethyl)benzylamine

[0359] Bis(2-hydroxyethyl)amine (5 g) was dissolved inN,N-dimethylformamide (100 ml), added with benzyl bromide (6.52 ml) andpotassium carbonate (8.657 g) and stirred at room temperature for 21hours. The reaction mixture was added with water (200 ml) and extractedtwice with dichloromethane (200 ml). The organic layer was dried overanhydrous magnesium sulfate, and then the solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (elution solvent: dichloromethane:methanol=20:1→10:1) toobtain 7.631 g of the title compound. Yield: 75%.

[0360]¹H-NMR (CDCl₃) δ (ppm); 2.34 (2H, br-s), 2.72 (4H, t, J=6 Hz),3.63 (4H, t, J=6 Hz), 3.71 (2H, s), 7.20-7.40 (5H, m)

[0361] MS (FAB); m/z 196 (MH⁺)

[0362] (b) 1-Benzyl-4-cyano-4-(2-methylphenyl)piperidine

[0363] Bis(2-hydroxyethyl)benzylamine (1 g) was dissolved indichloromethane (20 ml), added with thionyl chloride (1.9 ml) with icecooling and stirred at room temperature for 2.5 hours. The reactionmixture was added with water (10 ml) with ice cooling, and adjusted topH 7 with saturated aqueous sodium hydrogencarbonate. The layers wereseparated and the aqueous layer was further extracted withdichloromethane (20 ml). The organic layer was dried over anhydrousmagnesium sulfate, and then the solvent was evaporated under reducedpressure to obtain bis(2-chloroethyl)benzylamine (1.090 g).

[0364] 1-(2-Methylphenyl)acetonitrile (610 mg) was dissolved in dimethylsulfoxide (6.1 ml), added with sodium hydride (60%, in oil, 409 mg) andstirred at room temperature for 30 minutes. This reaction mixture wasadded with the solution of bis(2-chloroethyl)benzylamine (1.090 g)dissolved in dimethyl sulfoxide (6.1 ml) obtained above and furtherstirred at 75° C. for 2.5 hours. The reaction mixture was added withwater (50 ml) and extracted twice with ether (50 ml). The organic layerwas dried over anhydrous magnesium sulfate, and then the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (elution solvent: hexane:ethyl acetate=6:1) toobtain 1.077 g of the title compound. Yield: 80%.

[0365]¹H-NMR (CDCl₃) δ (ppm); 2.07 (2H, td, J=12 Hz, 3 Hz), 2.32 (2H,dd, J=12 Hz, 3 Hz), 2.59 (2H, t, J=12 Hz), 2.64 (3H, s), 3.01 (2H, d,J=12 Hz), 3.61 (2H, s), 7.20-7.40 (9H, m)

[0366] MS (TSP); m/z 291 (MH⁺)

[0367] (c) 4-Cyano-1-(ethoxycarbonyl)-4-(2-methylphenyl)piperidine

[0368] The title compound was obtained in the same manner in ReferenceExample 11(b) from 1-benzyl-4-cyano-4-(2-methylphenyl)piperidine. Yield:100%.

[0369]¹H-NMR (CDCl₃) δ (ppm); 1.28 (3H, t, J=7 Hz), 1.92 (2H, td, J=12Hz, 3 Hz), 2.34 (2H, d, J=12 Hz), 2.66 (3H, s), 3.33 (2H, m), 4.16 (2H,q, J=7 Hz), 4.34 (2H, m), 7.26 (4H, m)

[0370] MS (EI); m/z 272 (M⁺)

[0371] (d) 1-(Ethoxycarbonyl)-4-(ethoxycarbonylAminomethyl)-4-(2-methylphenyl)piperidine

[0372] 4-Cyano-1-(ethoxycarbonyl)-4-(2-methylphenyl)piperidine (504 mg)was dissolved in ethanol (10 ml), added with 10% palladium/carbon (500mg) and 5 N aqueous hydrochloric acid (0.74 ml) and stirred at roomtemperature for 15 hours under hydrogen gas pressure (30 psi) by usingthe Parr apparatus. After insoluble matters were removed by filtration,ethanol was evaporated under reduced pressure. The residue was addedwith dichloromethane (50 ml) and adjusted to pH 9 with saturated aqueoussodium hydrogencarbonate. The organic layer was separated, and theaqueous layer was further extracted with dichloromethane (50 ml). Theorganic layer was dried over anhydrous magnesium sulfate, and then thesolvent was evaporated under reduced pressure to obtain4-aminomethyl-1-(ethoxycarbonyl)-4-(2-methylphenyl)piperidine.

[0373] Subsequently, the resulting4-aminomethyl-1-(ethoxycarbonyl)-4-(2-methylphenyl)piperidine wasdissolved in dichloromethane (10 ml), added with ethyl chloroformate(0.18 ml) and triethylamine (0.26 ml) and stirred at room temperaturefor 30 minutes. After the reaction mixture was added with water (10 ml)and the layers were separated, the aqueous layer was further extractedwith dichloromethane (10 ml). The organic layer was dried over anhydrousmagnesium sulfate, and then the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(elution solvent: hexane:ethyl acetate=2:1) to obtain 372 mg of thetitle compound. Yield: 51% (for the two steps).

[0374]¹H-NMR (CDCl₃) δ (ppm); 1.10-1.30 (6H, m), 1.85 (2H, m), 2.31 (2H,m), 2.51 (3H, s), 3.26 (2H, m), 3.53 (1H, s), 3.55 (1H, s), 3.74 (2H,m), 4.00-4.20 (4H, m), 4.29 (1H, br-s), 7.15-7.30 (4H, m)

[0375] MS (TSP); m/z 349 (MH⁺)

[0376] (e)1′-(Tert-Butoxycarbonyl)-2,3-dihydro-5-methylspiro[isoquinoline-4(1H),4′-piperidin]-1-one

[0377]1-(Ethoxycarbonyl)-4-(ethoxycarbonylaminomethyl)-4-(2-methylphenyl)piperidine(327 mg) was dissolved in polyphosphoric acid (6.5 g) and stirred at150° C. for 2 hours. The reaction mixture was added with ice (30 g),adjusted to pH 12 with 5 N aqueous sodium hydroxide and then extractedtwice with dichloromethane (30 ml). The organic layer was dried overanhydrous magnesium sulfate, and then the solvent was evaporated underreduced pressure, and the residue was dissolved in dichloromethane (10ml). The reaction mixture was added with di-tert-butyl dicarbonate (0.43ml) and triethylamine (0.26 ml) and stirred at room temperature for 1hour. After the reaction mixture was added with water (10 ml) and thelayers were separated, the aqueous layer was further extracted withdichloromethane (10 ml). The organic layer was dried over anhydrousmagnesium sulfate, and then the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(elution solvent: hexane:ethyl acetate=1:2 ethyl acetate) to obtain 102mg of the title compound. Yield: 33% (for the two steps).

[0378]¹H-NMR (CDCl₃) δ (ppm); 1.49 (9H, m), 1.73 (2H, d, J=12 Hz), 2.41(2H, m), 2.56 (3H, s), 2.99 (2H, t, J=12 Hz), 3.59 (2H, s), 4.04 (2H,m), 6.17 (1H, br-s), 7.25-7.35 (2H, m), 8.04 (1H, d, J=8 Hz)

[0379] MS (TSP); m/z 331 (MH⁺)

[0380] (f)2,3-Dihydro-5-methylspiro[isoquinoline-4(1H),4′-piperidin]-1-oneTrifluoroacetate

[0381] The title compound was obtained in the same manner in ReferenceExample 3(c) from1′-(tert-butoxycarbonyl)-2,3-dihydro-5-methylspiro[isoquinoline-4(1H),4′-piperidin]-1-one.Yield: 100%.

[0382]¹H-NMR (D₂O) δ (ppm); 1.96 (2H, d, J=14 Hz), 2.60 (3H, s), 2.70(2H, td, J=14 Hz, 4 Hz), 3.26 (2H, t, J=14 Hz), 3.43 (2H, dd, J=14 Hz, 4Hz), 3.63 (2H, s), 7.36 (1H, t, J=8 Hz), 7.46 (1H, d, J=8 Hz), 7.84 (1H,d, J=8 Hz)

[0383] MS (EI); m/z 230 (M⁺)

Reference Example 134-(2-Hydroxymethyl-7-methyl-1H-benzimidazol-1-yl)piperidine

[0384] The1-Ethoxycarbonyl-4-(1,3-dihydro-7-methyl-2H-benzimidazol-2-on-1-yl)piperidine(40 mg) obtained in Reference Example 11, (d) was dissolved in 5 Naqueous hydrochloric acid (0.8 ml), added with glycolic acid (16 mg) andstirred at 100° C. for 3 days. The reaction mixture was made alkaline byaddition of aqueous ammonia and extracted twice with dichloromethane (2ml). The organic layer was dried over anhydrous magnesium sulfate, andthen the solvent was evaporated under reduced pressure to obtain 14.4 mgof the title compound. Yield: 41%.

[0385]¹H-NMR (CDCl₃) δ (ppm); 1.90 (2H, m), 2.42 (2H, m), 2.59 (3H, s),2.82 (2H, m), 3.28 (2H, m), 4.57 (1H, m), 4.93 (2H, s), 7.01 (1H, d, J=8Hz), 7.12 (1H, t, J=8 Hz), 7.48 (1H, d, J=8 Hz)

[0386] MS (EI); m/z 245 (M⁺)

Reference Example 141-[2-(4-Isobutyloxycarbonylbenzyl)phenoxy]acetaldehyde

[0387] (a) 4-Formyloxymethylbenzoic Acid

[0388] Formic acid (1.24 ml) and acetic anhydride (0.62 ml) were mixedand stirred at 50° C. for 30 minutes. This solution was cooled to 0° C.,added with 4-hydroxymethylbenzoic acid (500 mg) and stirred at roomtemperature for 4.5 hours. The reaction mixture was added with water (5ml) and extracted twice with ethyl acetate (5 ml). The organic layer wasdried over anhydrous magnesium sulfate, and then the solvent wasevaporated under reduced pressure to obtain 536 mg of the titlecompound. Yield: 91%.

[0389]¹H-NMR (DMSO-d₆) δ (ppm); 5.24 (2H, s), 7.49 (2H, d, J=8 Hz), 7.94(2H, d, J=8 Hz), 8.40 (1H, s), 13.01 (1H, s)

[0390] (b) 4-(Formyloxymethyl)-N-(1,1-dimethyl-2-hydroxyethyl)benzamide

[0391] 4-Formyloxymethylbenzoic acid (100 mg) was added with thionylchloride (0.2 ml) and stirred at 80° C. for 1 hour. The solvent wasevaporated under reduced pressure to obtain an acid chloride.

[0392] Separately, 2-amino-2-methylpropanol (53 μl) was dissolved indichloromethane (1 ml), added with a solution of the aforementioned acidchloride dissolved in dichloromethane (1 ml) at 0° C. and triethylamine(77 μl) and stirred at the same temperature for 1 hour. The reactionmixture was added with water (5 ml) and extracted twice withdichloromethane (5 ml). The organic layer was dried over anhydrousmagnesium sulfate, and then the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(elution solvent: hexane:ethyl acetate=1:2) to obtain 64.5 mg of thetitle compound. Yield: 46%.

[0393]¹H-NMR (CDCl₃) δ (ppm); 1.42 (6H, s), 3.70 (1H, d, J=6 Hz), 4.54(1H, d, J=6 Hz), 5.24 (2H, s), 6.19 (1H, m), 7.44 (2H, d, J=8 Hz), 7.74(2H, d, J=8 Hz), 8.16 (1H, s)

[0394] MS (TSP); m/z 252 (MH⁺)

[0395] (c) 4-(4,4-Dimethyloxazolin-2-yl)-1-(formyloxymethyl)benzene

[0396] 4-(Formyloxymethyl)-N-(1,1-dimethyl-2-hydroxyethyl)benzamide (64mg) was added with thionyl chloride (56 μl) and stirred at roomtemperature for 30 minutes. The solvent was evaporated under reducedpressure, and then the residue was added with water (5 ml) and extractedtwice with ethyl acetate (5 ml). The organic layer was dried overanhydrous magnesium sulfate, and then the solvent was evaporated underreduced pressure. The residue was purified by preparative thin layersilica gel column chromatography (developing solvent: hexane:ethylacetate=2:1) to obtain 37.4 mg of the title compound. Yield: 63%.

[0397]¹H-NMR (CDCl₃) δ (ppm); 1.38 (6H, s), 4.11 (2H, m), 5.23 (2H, s),7.40 (2H, d, J=8 Hz), 7.95 (2H, d, J=8 Hz), 8.16 (1H, s)

[0398] MS (EI); m/z 232 (M⁺)

[0399] (d) 4-(4,4-Dimethyloxazolin-2-yl)benzyl Alcohol

[0400] 4-(4,4-Dimethyloxazolin-2-yl)-1-(formyloxymethyl)benzene (37 mg)was dissolved in methanol (0.4 ml), added with 1 N aqueous sodiumhydroxide (0.18 ml) and stirred at room temperature for 20 minutes. Thereaction mixture was added with water (5 ml) and extracted twice withethyl acetate (5 ml). The organic layer was dried over anhydrousmagnesium sulfate, and then the solvent was evaporated under reducedpressure. The residue was purified by preparative thin layer silica gelcolumn chromatography (developing solvent: hexane:ethyl acetate=1:2) toobtain 17.7 mg of the title compound. Yield: 54%.

[0401]¹H-NMR (CDCl₃) δ (ppm); 1.37 (6H, s), 4.10 (2H, s), 4.71 (2H, s),7.35 (2H, d, J=8 Hz), 7.85 (2H, d, J=8 Hz)

[0402] (e) 4-(4,4-Dimethyloxazolin-2-yl)benzaldehyde

[0403] The title compound was obtained in the same manner in ReferenceExample 1(b) from 4-(4,4-dimethyloxazolin-2-yl)benzyl alcohol. Yield:73%.

[0404]¹H-NMR (CDCl₃) δ (ppm); 1.41 (6H, s), 4.15 (2H, s), 7.92 (2H, d,J=8 Hz), 8.11 (2H, d, J=8 Hz), 10.07 (1H, s)

[0405] (f)1-[4-(4,4-Dimethyloxazolin-2-yl)phenyl]-1-(2-methoxyphenyl)methylAlcohol

[0406] The title compound was obtained in the same manner in ReferenceExample 1(c) from 4-(4,4-dimethyloxazolin-2-yl)benzaldehyde. Yield: 81%.

[0407]¹H-NMR (CDCl₃) δ (ppm); 1.37 (6H, s), 3.18 (1H, d, J=6 Hz), 3.79(3H, s), 4.09 (2H, s), 6.06 (1H, d, J=6 Hz), 6.88 (1H, d, J=8 Hz), 6.94(1H, t, J=8 Hz), 7.20 (1H, d, J=8 Hz), 7.27 (1H, t, J=8 Hz), 7.42 (2H,d, J=8 Hz), 7.89 (2H, d, J=8 Hz)

[0408] (g) 2-[4-(4,4-Dimethyloxazolin-2-yl)benzyl]anisole

[0409] 1-[4-(4,4-Dimethyloxazolin-2-yl)phenyl]-1-(2-methoxyphenyl)methylalcohol (100 mg) was dissolved in pyridine (0.4 ml), added with aceticanhydride (0.25 ml) with ice cooling and stirred at room temperature for4 hours. After the reaction mixture was added with methanol (0.25 ml)with ice cooling and stirred at room temperature for 10 minutes, thesolvent was evaporated under reduced pressure to obtain1-[4-(4,4-dimethyloxazolin-2-yl)phenyl]-1-(2-methoxyphenyl)methylacetate.

[0410] In an amount of 23.5 mg of the1-[4-(4,4-dimethyloxazolin-2-yl)phenyl]-1-(2-methoxyphenyl)methylacetate obtained above was dissolved in methanol (0.47 ml), added with10% palladium/carbon (24 mg) and ammonium formate (42 mg) under argonatmosphere and stirred at 60° C. for 2 hours. After insoluble matterswere removed by filtration, the solvent was evaporated under reducedpressure. The residue was purified by preparative thin layer silica gelcolumn chromatography (developing solvent: hexane:ethyl acetate=1:1) toobtain 14.4 mg of the title compound. Yield: 73%.

[0411]¹H-NMR (CDCl₃) δ (ppm); 1.36 (6H, s), 3.79 (3H, s), 3.99 (2H, s),4.08 (2H, s), 6.87 (2H, t, J=8 Hz), 7.05 (1H, d, J=8 Hz), 7.20-7.25 (3H,m), 7.83 (2H, d, J=8 Hz)

[0412] MS (TSP); m/z 296 (MH⁺)

[0413] (h) 2-(4-Carboxybenzyl)anisole

[0414] 2-[4-(4,4-Dimethyloxazolin-2-yl)benzyl]anisole (22.3 mg) wasdissolved in 5 N aqueous hydrochloric acid (2.2 ml) and stirred at 100°C. for 8 hours. The reaction mixture was extracted twice withdichloromethane (4 ml), and the organic layer was dried over anhydrousmagnesium sulfate. Then, the solvent was evaporated under reducedpressure to obtain 15.3 mg of the title compound. Yield: 84%.

[0415]¹H-NMR (CDCl₃) δ (ppm); 3.80 (3H, s), 4.03 (2H, s), 6.89 (2H, m),7.09 (1H, d, J=8 Hz), 7.22 (1H, t, J=8 Hz), 7.30 (2H, d, J=8 Hz), 8.00(2H, d, J=8 Hz)

[0416] MS (TSP, negative); m/z 241 (M-H⁻)

[0417] (i) 2-(4-Carboxybenzyl)phenol

[0418] The title compound was obtained in the same manner in ReferenceExample 5, (c) from 2-(4-carboxybenzyl)anisole. Yield: 60%.

[0419]¹H-NMR (DMSO-d₆) δ (ppm); 3.91 (2H, s), 6.71 (1H, t, J=8 Hz), 6.80(1H, d, J=8 Hz), 7.04 (2H, m), 7.31 (2H, d, J=8 Hz), 7.82 (2H, d, J=8Hz)

[0420] MS (EI); m/z 228 (M⁺)

[0421] (j) 2-(4-Isobutyloxycarbonylbenzyl)phenol

[0422] 2-(4-Carboxybenzyl)phenol (603 mg) was dissolved in isobutanol (3ml), added with sulfuric acid (0.6 ml) and stirred at 80° C. for 3hours. The reaction mixture was added with water (5 ml) and extractedtwice with ethyl acetate (5 ml). The organic layer was dried overanhydrous magnesium sulfate, and then the solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (elution solvent: hexane:ethyl acetate=5:1) to obtain 318mg of the title compound. Yield: 42%.

[0423]¹H-NMR (CDCl₃) δ (ppm); 1.00 (6H, d, J=7 Hz), 2.06 (1H, m), 4.04(2H, s), 4.09 (2H, d, J=7 Hz), 6.78 (1H, d, J=8 Hz), 6.89 (1H, t, J=8Hz), 7.12 (2H, m), 7.30 (2H, d, J=8 Hz), 7.96 (2H, d, J=8 Hz)

[0424] MS (FAB); m/z 285 (MH⁺)

[0425] (k)1-[2-(4-Isobutyloxycarbonylbenzyl)phenoxy]-2,3-dihydroxypropane

[0426] The title compound was obtained in the same manner in ReferenceExample 2(a) from 2-(4-isobutyloxycarbonylbenzyl)phenol. Yield: 61%.

[0427]¹H-NMR (CDCl₃) δ (ppm); 1.01 (6H, d, J=7 Hz), 1.94 (1H, s), 2.06(1H, m), 2.19 (1H, s), 3.60 (1H, m), 3.70 (1H, m), 3.98 (3H, m), 4.03(2H, s), 4.07 (2H, d, J=7 Hz), 6.86 (1H, d, J=8 Hz), 6.96 (1H, t, J=8Hz), 7.16 (2H, d, J=8 Hz), 7.23 (2H, m), 7.96 (2H, d, J=8 Hz)

[0428] (l) 1-[2-(4-Isobutyloxycarbonylbenzyl)phenoxy]acetaldehyde

[0429] The title compound was obtained in the same manner in ReferenceExample 2(b) from1-[2-(4-isobutyloxycarbonylbenzyl)phenoxy]-2,3-dihydroxypropane. Yield:96%.

[0430]¹H-NMR (CDCl₃) δ (ppm); 1.01 (6H, d, J=7 Hz), 2.06 (1H, m), 4.08(2H, d, J=7 Hz), 4.11 (2H, s), 4.53 (2H, s), 6.72 (1H, d, J=8 Hz), 6.98(1H, t, J=8 Hz), 7.20 (2H, m), 7.29 (2H, d, J=8 Hz), 7.95 (2H, d, J=8Hz), 9.75 (1H, s)

[0431] MS (FAB); m/z 327 (MH⁺)

Reference Example 151-[2-[4-(2-Methylbutyryl)benzyl]phenoxy]acetaldehyde

[0432] (a) 2-[4-(2-Methylbutyryl)benzyl]anisole

[0433] The 2-(4-diethylcarbamoylbenzyl)anisole (100 mg) obtained in theprocess of Reference Example 1(d) was dissolved in toluene (2 ml), addedwith a solution of sec-butyl lithium in n-hexane and cyclohexane (1.0 M,0.47 ml) at 0° C. under argon atmosphere and stirred at room temperaturefor 1 hour. After the reaction mixture was slowly poured into 1 Naqueous hydrochloric acid (5 ml) with ice cooling to quench the reactionand the layers were separated, the aqueous layer was extracted withether (10 ml). The organic layer was washed with saline and dried overanhydrous magnesium sulfate, and then the solvent was evaporated underreduced pressure. The residue was purified by preparative thin layersilica gel column chromatography (developing solvent: hexane:ethylacetate=2:1) to obtain 58.3 mg of the title compound. Yield: 61%.

[0434]¹H-NMR (CDCl₃) δ (ppm); 0.90 (3H, t, J=7 Hz), 1.17 (3H, d, J=7Hz), 1.46 (1H, m), 1.81 (1H, m), 3.36 (1H, m), 3.80 (3H, s), 4.01 (2H,s), 6.89 (2H, m), 7.09 (1H, d, J=8 Hz), 7.22 (1H, t, J=8 Hz), 7.29 (2H,d, J=8 Hz), 7.86 (2H, d, J=8 Hz)

[0435] MS (EI); m/z 282 (M⁺)

[0436] (b) 2-[4-(2-Methylbutyryl)benzyl]phenol

[0437] The title compound was obtained in the same manner in ReferenceExample 5, (c) from 2-[4-(2-methylbutyryl)benzyl]anisole. Yield: 87%.

[0438]¹H-NMR (CDCl₃) δ (ppm); 0.90 (3H, t, J=7 Hz), 1.17 (3H, d, J=7Hz), 1.47 (1H, m), 1.82 (1H, m), 3.36 (1H, m), 4.04 (2H, s), 6.79 (1H,d, J=8 Hz), 6.90 (1H, t, J=8 Hz), 7.13 (2H, m), 7.32 (2H, d, J=8 Hz),7.87 (2H, d, J=8 Hz)

[0439] MS (TSP); m/z 269 (MH⁺)

[0440] (c) 1-[2-[4-(2-Methylbutyryl)benzyl]phenoxy]-2,3-dihydroxypropane

[0441] The title compound was obtained in the same manner in ReferenceExample 2(a) from 2-[4-(2-methylbutyryl)benzyl]phenol. Yield: 63%.

[0442]¹H-NMR (CDCl₃) δ (ppm); 0.90 (3H, t, J=7 Hz), 1.17 (3H, d, J=7Hz), 1.47 (1H, m), 1.81 (1H, m), 1.92 (1H, s), 2.17 (1H, s), 3.35 (1H,m), 3.60 (1H, m), 3.70 (1H, m), 3.99 (2H, s), 4.03 (3H, m), 6.86 (1H, d,J=8 Hz), 6.96 (1H, t, J=8 Hz), 7.17 (2H, d, J=8 Hz), 7.26 (2H, d, J=8Hz), 7.86 (2H, d, J=8 Hz)

[0443] MS (TSP); m/z 343 (MH⁺)

[0444] (d) 1-[2-[4-(2-Methylbutyryl)benzyl]phenoxy]acetaldehyde

[0445] The title compound was obtained in the same manner in ReferenceExample 2(b) from1-[2-[4-(2-methylbutyryl)benzyl]phenoxy]-2,3-dihydroxypropane. Yield:85%.

[0446]¹H-NMR (CDCl₃) δ (ppm); 0.90 (3H, t, J=7 Hz), 1.17 (3H, d, J=7Hz), 1.47 (1H, m), 1.81 (1H, m), 3.36 (1H, m), 4.11 (2H, s), 4.54 (2H,s), 6.73 (1H, d, J=8 Hz), 6.99 (1H, t, J=8 Hz), 7.20 (2H, m), 7.32 (2H,d, J=8 Hz), 7.87 (2H, d, J=8 Hz), 9.76 (1H, s)

Reference Example 162-Benzyl-2,3-dihydro-5-methylspiro[isoquinoline-4(1H),4′-piperidin]-1-oneTrifluoroacetate

[0447] (a)2-Benzyl-1′-(tert-butoxycarbonyl)-2,3-dihydro-5-methylspiro[isoquinoline-4(1H),4′-piperidin]-1-one

[0448]1′-(tert-Butoxycarbonyl)-2,3-dihydro-5-methylspiro[isoquinoline-4(1H),4′-piperidin]-1-one(80.7 mg) was dissolved in toluene (1.6 ml), added with sodium hydroxide(powder, 34.2 mg), potassium carbonate (67.4 mg), tetrabutylammoniumhydrogensulfate (8.3 mg) and benzyl bromide (44 μl) and stirred at 70°C. for 3 hours. The reaction mixture was added with water (2 ml) andextracted twice with dichloromethane (2 ml). The organic layer was driedover anhydrous magnesium sulfate, and then the solvent was evaporatedunder reduced pressure. The residue was purified by preparative thinlayer silica gel column chromatography (developing solvent: hexane:ethylacetate=1:5) to obtain 86 mg of the title compound. Yield: 84%.

[0449]¹H-NMR (CDCl₃) δ (ppm); 1.44 (9H, s), 1.46 (2H, d, J=12 Hz),2.20-2.45 (4H, m), 2.50 (3H, s), 3.47 (2H, s), 3.77 (2H, m), 4.78 (2H,m), 7.25-7.40 (7H, m), 8.13 (1H, t, J=8 Hz)

[0450] MS (FAB); m/z 421 (MH⁺)

[0451] (b)2-Benzyl-2,3-dihydro-5-methylspiro[isoquinoline-4(1H),4′-piperidin]-1-oneTrifluoroacetate

[0452] The title compound was obtained in the same manner in ReferenceExample 3(c) from2-benzyl-1′-(tert-butoxycarbonyl)-2,3-dihydro-5-methylspiro[isoquinoline-4(1H),4′-piperidin]-1-one.Yield: 100%.

Example 11-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]-4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine

[0453] 4-(1,3-Dihydro-2H-benzimidazol-2-on-1-yl)piperidine (27.2 mg) wasdissolved in dichloroethane (0.6 ml), added with the1-[2-(4-diethylcarbamoylbenzyl)phenoxy]acetaldehyde (50.4 mg) obtainedin Reference Example 2, sodium triacetoxyborohydride (39.7 mg) andacetic acid (0.12 ml) and stirred at room temperature for 18 hours. Thereaction mixture was added with saturated aqueous sodiumhydrogencarbonate (2 ml) and extracted twice with dichloromethane (2ml). The organic layer was dried over anhydrous magnesium sulfate, andthen the solvent was evaporated under reduced pressure. The residue wasby purified preparative thin layer silica gel column chromatography(developing solvent: ethyl acetate:methanol=20:1) to obtain 29.8 mg ofthe title compound. Yield: 45%.

[0454]¹H-NMR (CDCl₃) δ (ppm); 1.10 (3H, br-s),1.18 (3H, br-s), 1.80 (2H,m),2.30-2.60 (4H, m), 2.86 (2H, t, J=5 Hz), 3.15-3.35 (4H, m), 3.50 (2H,br-s), 4.00 (2H, s), 4.15 (2H, t, J=5 Hz), 4.38 (1H, m), 6.85-6.95 (2H,m), 7.00-7.15 (4H, m), 7.20-7.35 (6H, m), 9.41 (1H, s)

[0455] MS (TSP); m/z 527 (MH⁺)

Example 21-[3-[2-(4-Diethylcarbamoylbenzyl)phenoxy]propyl]-4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine

[0456] 4-(1,3-Dihydro-2H-benzimidazol-2-on-1-yl)piperidine (49 mg) wasdissolved in methyl ethyl ketone (1.8 ml), added with the1-bromo-3-[2-(4-diethylcarbamoylbenzyl)phenoxy]propane (91 mg) obtainedin Reference Example 1 and triethylamine (47 μl) and stirred at roomtemperature for 17 hours. The reaction mixture was added with water (2ml) and extracted twice with ethyl acetate (2 ml). The organic layer wasdried over anhydrous magnesium sulfate, and then the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (elution solvent:dichloromethane:methanol=20:1) to obtain 49.7 mg of the title compound.Yield: 41%.

[0457]¹H-NMR (CDCl₃) δ (ppm); 1.11 (3H, br-s), 1.21 (3H, br-s), 1.82(2H, m), 1.99 (2H, m), 2.15 (2H, m), 2.46 (2H, m), 2.53 (2H, t, J=5 Hz),3.07 (2H, m), 3.26 (2H, br-s), 3.51 (2H, br-s), 4.00 (2H, s), 4.04 (2H,t, J=5 Hz), 4.37 (1H, m), 6.90 (2H, m), 7.03-7.12 (4H, m), 7.20-7.28(6H, m), 9.66 (1H, s)

[0458] MS (EI); m/z 541 (M⁺)

Example 38-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one

[0459] The title compound was obtained in the same manner in Example 1from the 1-[2-(4-diethylcarbamoylbenzyl)phenoxy]acetaldehyde obtained inReference Example 2 and 1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one.Yield: 29%.

[0460]¹H-NMR (CDCl₃) δ (ppm); 1.10 (3H, br-s), 1.25 (3H, br-s), 1.69(2H, d, J=14 Hz), 2.70 (2H, m), 2.94 (6H, m), 3.24 (2H, br-s), 3.51 (2H,br-s), 3.99 (2H, s), 4.18 (2H, m), 4.72 (2H, s), 6.80-7.00 (6H, m),7.05-7.30 (8H, m)

[0461] MS (TSP); m/z 541 (MH⁺)

Example 43-Benzyl-8-[2-[2-(4-diethylcarbamoylbenzyl)phenoxy]ethyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one

[0462] The title compound was obtained in the same manner in Example 1from the 1-[2-(4-diethylcarbamoylbenzyl)phenoxy]acetaldehyde obtained inReference Example 2 and the3-benzyl-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one trifluoroacetateobtained in Reference Example 3. Yield: 50%.

[0463]¹H-NMR (CDCl₃) δ (ppm); 1.09 (3H, br-s), 1.20 (3H, br-s), 1.69(2H, d, J=14 Hz), 2.60-3.30 (10H, m), 3.50 (2H, br-s), 4.00 (2H, s),4.19 (2H, m), 4.58 (2H, s), 4.60 (2H, s), 6.75-6.95 (6H, m), 7.05-7.40(12H, m)

[0464] MS (TSP); m/z 631 (MH⁺)

Example 53-Cyclopropylmethyl-8-[2-[2-(4-diethylcarbamoylbenzyl)phenoxy]ethyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one

[0465] The title compound was obtained in the same manner in Example 1from the 1-[2-(4-diethylcarbamoylbenzyl)phenoxy]acetaldehyde obtained inReference Example 2 and3-cyclopropylmethyl-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-onetrifluoroacetate obtained in the same manner in Reference Example 3.Yield: 49%.

[0466]¹H-NMR (CDCl₃) δ (ppm); 0.29 (2H, m), 0.59 (2H, m), 1.00 (1H, m),1.10 (3H, br-s), 1.18 (3H, br-s), 1.66 (2H, d, J=14 Hz), 2.70-3.30 (10H,m), 3.30 (2H, d, J=7 Hz), 3.50 (2H, br-s), 3.98 (2H, s), 4.25 (2H, m),4.80 (2H, s), 6.75-7.00 (6H, m), 7.05-7.35 (7H, m)

[0467] MS (TSP); m/z 595 (MH⁺)

Example 61-[4-[2-(4-Diethylcarbamoylbenzyl)phenoxy]butyl]-4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine

[0468] The title compound obtained in the same manner in Example 2 from1-bromo-4-[2-(4-diethylcarbamoylbenzyl)phenoxy]butane obtained in thesame manner in Reference Example 1 and4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine. Yield: 37%.

[0469]¹H-NMR (CDCl₃) δ (ppm); 1.10 (3H, br-s), 1.20 (3H, br-s), 1.69(2H, m), 1.82 (4H, m), 2.35 (2H, m), 2.46 (4H, m), 3.10 (2H, m), 3.26(2H, br-s), 3.51 (2H, br-s), 4.00 (4H, m), 4.40 (1H, m), 6.88 (2H, m),7.03 (2H, m), 7.09 (2H, m), 7.18-7.29 (6H, m), 9.81 (1H, s)

[0470] MS (EI); m/z 554 (M⁺)

Example 78-[4-[2-(4-Diethylcarbamoylbenzyl)phenoxy]butyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one

[0471] The title compound was obtained in the same manner in Example 2from 1-bromo-4-[2-(4-diethylcarbamoylbenzyl)phenoxy]butane obtained inthe same manner in Reference Example 1 and1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one. Yield: 44%.

[0472]¹H-NMR (CDCl₃) δ (ppm); 1.09 (3H, br-s), 1.20 (3H, br-s), 1.68(6H, m), 2.58 (2H, m), 2.91 (6H, m), 3.26 (2H, br-s), 3.50 (2H, br-s),3.99 (4H, m), 4.72 (2H, s), 6.85 (3H, m), 6.95 (2H, m), 7.09 (1H, m),7.16-7.30 (8H, m)

[0473] MS (EI); m/z 568 (M⁺)

Example 88-[3-[2-(4-diethylcarbamoylbenzyl)phenoxy]propyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one

[0474] The title compound was obtained in the same manner in Example 2from the 1-bromo-3-[2-(4-diethylcarbamoylbenzyl)phenoxy]propane obtainedin Reference Example 1 and 1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one.Yield: 48%.

[0475]¹H-NMR (CDCl₃) δ (ppm); 1.11 (3H, br-s), 1.21 (3H, br-s), 1.76(4H, m), 2.06 (2H, m), 2.64 (2H, m), 2.92 (4H, m), 3.26 (2H, br-s), 3.51(2H, br-s), 3.98 (2H, s), 4.03 (2H, t, J=5 Hz), 4.72 (2H, s), 6.70-7.30(14H, m)

[0476] MS (EI); m/z 554 (M⁺)

Example 91-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]-4-(3-benzyl-1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine

[0477] The title compound was obtained in the same manner in Example 1from the 1-[2-(4-diethylcarbamoylbenzyl)phenoxy]acetaldehyde obtained inReference Example 2 and4-(3-benzyl-1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidinetrifluoroacetate obtained in the same manner in Reference Example 3.Yield: 50%.

[0478]¹H-NMR (CDCl₃) δ (ppm); 1.09 (3H, br-s), 1.19 (3H, br-s), 1.83(2H, d, J=14 Hz), 2.30-2.55 (4H, m), 2.84 (2H, t, J=5 Hz), 3.15 (2H, d,J=12 Hz), 3.24 (2H, br-s), 3.49 (2H, br-s), 4.00 (2H, s), 4.13 (2H, t,J=5 Hz), 4.45 (1H, m), 5.06 (2H, s), 6.85-7.40 (17H, m)

[0479] MS (TSP); m/z 617 (MH⁺)

Example 101-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]-4-(3-cyclopropylmethyl-1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine

[0480] The title compound was obtained in the same manner in Example 1from the 1-[2-(4-diethylcarbamoylbenzyl)phenoxy]acetaldehyde obtained inReference Example 2 and4-(3-cyclopropylmethyl-1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidinetrifluoroacetate obtained in the same manner in Reference Example 3.Yield: 71%.

[0481]¹H-NMR (CDCl₃) δ (ppm); 0.42 (2H, m), 0.55 (2H, m), 1.05-1.30 (7H,m), 1.80 (2H, m), 2.25-2.55 (4H, m), 2.84 (2H, t, J=5 Hz), 3.14 (2H, d,J=12 Hz), 3.24 (2H, br-s), 3.50 (2H, br-s), 3.75 (2H, d, J=7 Hz), 4.00(2H, s), 4.12 (2H, t, J=5 Hz), 4.41 (1H, m), 6.85-6.95 (2H, m),7.05-7.10 (4H, m), 7.15-7.35 (6H, m)

[0482] MS (FAB); m/z 581 (MH⁺)

Example 111′-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]hexahydrospiro-[imidazo[1,2-a]pyridine-3(2H),4′-piperidin]-2-one

[0483] The title compound was obtained in the same manner in Example 1from the 1-[2-(4-diethylcarbamoylbenzyl)phenoxy]acetaldehyde obtained inReference Example 2 andhexahydrospiro[imidazo[1,2-a]pyridine-3(2H),4′-piperidin]-2-onesynthesized in accordance with the descriptions of Yakugaku Zasshi,1989, 109, 93. Yield: 38%.

[0484]¹H-NMR (CDCl₃) δ (ppm); 1.12 (3H, br-s), 1.21 (3H, br-s), 1.35(2H, m), 1.51 (1H, m), 1.67 (5H, m), 1.83 (2H, m), 2.39 (1H, td, J=12Hz, 3 Hz), 2.63 (1H, m), 2.85 (5H, m), 3.10-3.35 (3H, m), 3.51 (2H,br-s), 3.94 (1H, m), 3.97 (2H, s), 4.11 (2H, m), 5.81 (1H, s), 6.80-6.95(2H, m), 7.08 (1H, d, J=8 Hz), 7.15-7.30 (5H, m)

[0485] MS (FAB); m/z 519 (MH⁺)

Example 121′-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]-5,6,7,8-tetrahydrospiro[imidazo[1,2-a]pyridine-3(2H),4′-piperidin]-2-one

[0486] The title compound was obtained in the same manner in Example 1from the 1-[2-(4-diethylcarbamoylbenzyl)phenoxy]acetaldehyde obtained inReference Example 2 and5,6,7,8-tetrahydrospiro[imidazo[1,2-a]pyridine-3(2H),4′-piperidin]-2-onesynthesized in accordance with the descriptions of Yakugaku Zasshi,1989, 109, 93. Yield: 68%.

[0487]¹H-NMR (CDCl₃) δ (ppm); 1.11 (3H, br-s), 1.21 (3H, br-s), 1.57(2H, d, J=12 Hz), 1.75-2.00 (6H, m), 2.70-2.85 (4H, m), 2.91 (2H, t, J=5Hz), 3.15 (2H, t, J=12 Hz), 3.23 (4H, m), 3.51 (2H, m), 3.98 (2H, s),4.11 (2H, t, J=5 Hz), 6.80-6.90 (2H, m), 7.10 (1H, d, J=8 Hz), 7.15-7.30(5H, m)

[0488] MS (FAB); m/z 517 (MH⁺)

Example 131-[2-[2-(4-Dimethylcarbamoylbenzyl)phenoxy]ethyl]-4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine

[0489] The title compound was obtained in the same manner in Example 1from 1-[2-(4-dimethylcarbamoylbenzyl)phenoxy]acetaldehyde obtained inthe same manner in Reference Example 2 and4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine. Yield: 64%.

[0490]¹H-NMR (CDCl₃) δ (ppm); 1.81 (2H, m), 2.33 (2H, m), 2.47 (2H, m),2.86 (2H, t, J=5 Hz), 2.96 (3H, br-s), 3.07 (3H, br-s), 3.14 (2H, m),4.01 (2H, s), 4.13 (2H, t, J=5 Hz), 4.35 (1H, m), 6.90 (2H, m),7.02-7.12 (4H, m), 7.19-7.25 (4H, m), 7.32 (2H, m), 9.92 (1H, s)

[0491] MS (FAB); m/z 499 (MH⁺)

Example 148-[2-[2-(4-Dimethylcarbamoylbenzyl)phenoxy]ethyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one

[0492] The title compound was obtained in the same manner in Example 1from 1-[2-(4-dimethylcarbamoylbenzyl)phenoxy]acetaldehyde obtained inthe same manner in Reference Example 2 and1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one. Yield: 30%.

[0493]¹H-NMR (CDCl₃) δ (ppm); 2.63 (2H, m), 2.87 (6H, m), 2.95 (3H,br-s), 3.08 (5H, m), 4.00 (2H, s), 4.13 (2H, m), 4.72 (2H, s), 6.89 (6H,m), 7.08 (2H, m), 7.25 (6H, m)

[0494] MS (EI); m/z 512 (M⁺)

Example 154-(1,3-Dihydro-2H-benzimidazol-2-on-1-yl)-1-[2-[2-(4-pyrrolidinocarbonyl-benzyl)phenoxy]ethyl]piperidine

[0495] The title compound was obtained in the same manner in Example 1from 1-[2-(4-pyrrolidinocarbonylbenzyl)phenoxy]acetaldehyde obtained inthe same manner in Reference Example 2 and4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine. Yield: 48%.

[0496]¹H-NMR (CDCl₃) δ (ppm); 1.66 (2H, m), 1.81 (2H, m), 1.91 (2H, m),2.34 (2H, m), 2.46 (2H, m), 2.85 (2H, t, J=5 Hz), 3.14 (2H, m), 3.41(2H, t, J=7 Hz), 3.61 (2H, t, J=7 Hz), 4.01 (2H, s), 4.13 (2H, t, J=5Hz), 4.36 (1H, m), 6.90 (3H, m), 7.05 (3H, m), 7.22 (5H, m), 7.43 (1H,d, J=8 Hz)

[0497] MS (TSP); m/z 525 (MH⁺)

Example 161-Phenyl-8-[2-[2-(4-pyrrolidinocarbonylbenzyl)phenoxy]ethyl]-1,3,8-triazaspiro[4,5]decan-4-one

[0498] The title compound was obtained in the same manner in Example 1from 1-[2-(4-pyrrolidinocarbonylbenzyl)phenoxy]acetaldehyde obtained inthe same manner in Reference Example 2 and1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one. Yield: 27%.

[0499]¹H-NMR (CDCl₃) δ (ppm); 1.84 (2H, m), 1.92 (2H, m), 2.67 (2H, m),2.89 (2H, m), 2.99 (2H, m), 3.30 (2H, m), 3.41 (2H, t, J=7 Hz), 3.58(2H, m), 3.62 (2H, t, J=7 Hz), 4.01 (2H, s), 4.13 (2H, m), 4.71 (2H, s),6.80-7.43 (14H, m)

[0500] MS (TSP); m/z 539 (MH⁺)

Example 171-[2-[3-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]-4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine

[0501] The title compound was obtained in the same manner in Example 1from 1-[3-(4-diethylcarbamoylbenzyl)phenoxy]acetaldehyde obtained in thesame manner in Reference Example 2 and4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine. Yield: 49%.

[0502]¹H-NMR (CDCl₃) δ (ppm); 1.12 (3H, br-s), 1.21 (3H, br-s), 1.82(2H, m), 2.34 (2H, t, J=12 Hz), 2.51 (2H, q, J=12 Hz), 2.85 (2H, t, J=5Hz), 3.17 (2H, d, J=12 Hz), 3.27 (2H, br-s), 3.53 (2H, br-s), 3.97 (2H,s), 4.11 (2H, t, J=5 Hz), 4.39 (1H, m), 6.75-6.85 (3H, m), 7.00-7.15(3H, m), 7.20-7.35 (6H, m), 9.57 (1H, s)

[0503] MS (TSP); m/z 527 (MH⁺)

Example 188-[2-[3-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one

[0504] The title compound was obtained in the same manner in Example 1from 1-[3-(4-diethylcarbamoylbenzyl)phenoxy]acetaldehyde obtained in thesame manner in Reference Example 2 and1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one. Yield: 29%.

[0505]¹H-NMR (CDCl₃) δ (ppm); 1.12 (3H, br-s), 1.22 (3H, br-s), 1.72(2H, d, J=14 Hz), 2.70 (2H, m), 2.85-3.10 (6H, m), 3.26 (2H, br-s), 3.52(2H, br-s), 3.95 (2H, s), 4.11 (2H, t, J=5 Hz), 4.71 (2H, s), 6.70-7.00(6H, m), 7.15-7.35 (8H, m)

[0506] MS (TSP); m/z 541 (MH⁺)

Example 191-[2-[4-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]-4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine

[0507] The title compound was obtained in the same manner in Example 1from 1-[4-(4-diethylcarbamoylbenzyl)phenoxy]acetaldehyde obtained in thesame manner in Reference Example 2 and4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine. Yield: 49%.

[0508]¹H-NMR (CDCl₃) δ (ppm); 1.12 (3H, br-s), 1.22 (3H, br-s), 1.80(2H, m), 2.34 (2H, t, J=12 Hz), 2.51 (2H, q, J=12 Hz), 2.88 (2H, t, J=5Hz), 3.17 (2H, d, J=12 Hz), 3.27 (2H, br-s), 3.52 (2H, br-s), 3.94 (2H,s), 4.13 (2H, t, J=5 Hz), 4.39 (1H, m), 6.86 (2H, d, J=8 Hz), 7.00-7.15(4H, m), 7.18 (2H, d, J=8 Hz), 7.25-7.35 (4H, m), 9.52 (1H, s)

[0509] MS (TSP); m/z 527 (MH⁺)

Example 208-[2-[4-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one

[0510] The title compound was obtained in the same manner in Example 1from 1-[4-(4-diethylcarbamoylbenzyl)phenoxy]acetaldehyde obtained in thesame manner in Reference Example 2 and1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one. Yield: 36%.

[0511]¹H-NMR (CDCl₃) δ (ppm); 1.12 (3H, br-s), 1.21 (3H, br-s), 1.72(2H, d, J=14 Hz), 2.70 (2H, m), 2.85-3.10 (6H, m), 3.26 (2H, br-s), 3.52(2H, br-s), 3.93 (2H, s), 4.12 (2H, t, J=5 Hz), 4.72 (2H, s), 6.70-7.00(6H, m), 7.08 (2H, d, J=8 Hz), 7.18 (2H, d, J=8 Hz), 7.25-7.35 (4H, m)

[0512] MS (TSP); m/z 541 (MH⁺)

Example 214-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)-1-[2-[2-(4-piperidinocarbonylbenzyl)phenoxy]ethyl]piperidine

[0513] The title compound was obtained in the same manner in Example 1from 1-[2-(4-piperidinocarbonylbenzyl)phenoxy]acetaldehyde obtained inthe same manner in Reference Example 2 and4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine. Yield: 40%.

[0514]¹H-NMR (CDCl₃) δ (ppm); 1.47 (2H, m), 1.62 (4H, m), 1.81 (2H, m),2.38 (2H, m), 2.51 (2H, m), 2.89 (2H, t, J=5 Hz), 3.19 (2H, m), 3.31(2H, m), 3.68 (2H, m), 4.00 (2H, s), 4.17 (2H, t, J=5 Hz), 4.40 (1H, m),6.89 (2H, m), 7.03 (2H, m), 7.10 (2H, m), 7.19-7.30 (6H, m), 10.22 (1H,s)

[0515] MS (TSP); m/z 539 (MH⁺)

Example 221-Phenyl-8-[2-[2-(4-piperidinocarbonylbenzyl)phenoxy]ethyl]-1,3,8-triazaspiro[4,5]decan-4-one

[0516] The title compound was obtained in the same manner in Example 1from 1-[2-(4-piperidinocarbonylbenzyl)phenoxy]acetaldehyde obtained inthe same manner in Reference Example 2 and1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one. Yield: 14%.

[0517]¹H-NMR (CDCl₃) δ (ppm); 1.47 (2H, m), 1.61 (6H, m), 2.64 (2H, m),2.88 (4H, m), 2.96 (2H, m), 3.33 (2H, m), 3.67 (2H, m), 4.00 (2H, s),4.13 (2H, m), 4.73 (2H, s), 6.18 (1H, m), 6.88 (6H, m), 7.10 (1H, m),7.24 (6H, m)

[0518] MS (TSP); m/z 553 (MH⁺)

Example 231-[2-[2-(4-Diethylcarbamoylbenzoyl)phenoxy]ethyl]-4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine

[0519] The title compound was obtained in the same manner in Example 1from 1-[2-(4-diethylcarbamoylbenzoyl)phenoxy]acetaldehyde obtained inthe same manner in Reference Example 2 and4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine. Yield: 16%.

[0520]¹H-NMR (CDCl₃) δ (ppm); 1.09 (3H, br-s), 1.24 (3H, br-s), 1.73(2H, m), 2.15 (2H, m), 2.40 (2H, m), 2.56 (2H, m), 2.94 (2H, m), 3.21(2H, br-s), 3.55 (2H, br-s), 4.10 (2H, m), 4.29 (1H, m), 7.00-7.11 (6H,m), 7.43 (3H, m), 7.50 (1H, m), 7.83 (2H, d, J=8 Hz), 8.80 (1H, s)

[0521] MS (TSP); m/z 541 (MH⁺)

Example 248-[2-[2-(4-Diethylcarbamoylbenzoyl)phenoxy]ethyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one

[0522] The title compound was obtained in the same manner in Example 1from 1-[2-(4-diethylcarbamoylbenzoyl)phenoxy]acetaldehyde obtained inthe same manner in Reference Example 2 and1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one. Yield: 10%.

[0523]¹H-NMR (CDCl₃) δ (ppm); 1.10 (3H, br-s), 1.24 (3H, br-s), 1.60(2H, m), 2.58 (6H, m), 2.80 (2H, m), 3.22 (2H, br-s), 3.54 (2H, br-s),4.08 (2H, t, J=5 Hz), 4.70 (2H, s), 6.23 (1H, s), 6.88 (3H, m), 7.02(1H, d, J=8 Hz), 7.06 (1H, d, J=8 Hz), 7.27 (2H, m), 7.40 (3H, m), 7.48(1H, m), 7.81 (2H, d, J=8 Hz)

[0524] MS (TSP); m/z 555 (MH⁺)

Example 251-[2-[2-[1-(4-Diethylcarbamoylphenyl)-1-hydroxymethyl]phenoxy]ethyl]-4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine

[0525] The1-[2-[2-(4-diethylcarbamoylbenzoyl)phenoxy]ethyl]-4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine(39 mg) obtained in Example 23 was dissolved in ethanol (1 ml), addedwith sodium borohydride (1 mg) with ice cooling and stirred at roomtemperature for 30 minutes. The reaction mixture was added with water (5ml) and extracted twice with ethyl acetate (5 ml). The organic layer wasdried over anhydrous magnesium sulfate, and then the solvent wasevaporated under reduced pressure. The residue was purified bypreparative thin layer silica gel column chromatography (developingsolvent: ethyl acetate:methanol=10:1) to obtain 27.2 mg of the titlecompound. Yield: 70%.

[0526]¹H-NMR (CDCl₃) δ (ppm); 1.16 (3H, br-s), 1.26 (3H, br-s), 1.78(2H, m), 2.25 (2H, m), 2.70 (4H, m), 3.02 (1H, m), 3.21 (1H, m), 3.33(2H, br-s), 3.58 (2H, br-s), 4.23 (1H, m), 4.30 (1H, m), 4.44 (1H, m),6.19 (1H, s), 6.82 (1H, m), 6.89 (1H, t, J=8 Hz), 7.01 (4H, m), 7.44(2H, d, J=8 Hz), 7.57 (2H, d, J=8 Hz), 7.82 (2H, d, J=8 Hz), 8.73 (1H,s)

[0527] MS (TSP); m/z 543 (MH⁺)

Example 268-[2-[2-[1-(4-Diethylcarbamoylphenyl)-1-hydroxymethyl]phenoxy]ethyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one

[0528] The title compound was obtained in the same manner in Example 26from8-[2-[2-(4-diethylcarbamoylbenzoyl)phenoxy]ethyl]phenyl-1,3,8-triazaspiro[4,5]-decan-4-oneobtained in Example 24. Yield: 56%.

[0529]¹H-NMR (CDCl₃) δ (ppm); 1.14 (3H, br-s), 1.26 (3H, br-s), 1.69(2H, t, J=14 Hz), 2.78 (3H, m), 2.95 (5H, m), 3.31 (2H, br-s), 3.56 (2H,br-s), 4.26 (2H, m), 4.72 (2H, s), 6.13 (1H, s), 6.77 (3H, m), 6.89 (2H,d, J=8 Hz), 6.98 (1H, d, J=8 Hz), 7.03 (2H, d, J=8 Hz), 7.19 (2H, t, J=8Hz), 7.20 (2H, t, J=8 Hz), 7.56 (2H, d, J=8 Hz)

[0530] MS (TSP); m/z 557 (MH⁺)

Example 271-[2-[2-(3-Diethylcarbamoylbenzyl)phenoxy]ethyl]-4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine

[0531] The title compound was obtained in the same manner in Example 1from 1-[2-(3-diethylcarbamoylbenzyl)phenoxy]acetaldehyde obtained in thesame manner in Reference Example 2 and4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine. Yield: 44%.

[0532]¹H-NMR (CDCl₃) δ (ppm); 1.03 (3H, br-s), 1.21 (3H, br-s), 1.80(2H, d, J=12 Hz), 2.32 (2H, t, J=12 Hz), 2.46 (2H, q, J=12 Hz), 2.85(2H, t, J=5 Hz), 3.12 (2H, d, J=12 Hz), 3.19 (2H, br-s), 3.50 (2H,br-s), 4.01 (2H, s), 4.13 (2H, t, J=5 Hz), 4.37 (1H, m), 6.85-6.95 (2H,m), 7.00-7.30 (10H, m), 9.83 (1H, s)

[0533] MS (TSP); m/z 527 (MH⁺)

Example 288-[2-[2-(3-Diethylcarbamoylbenzyl)phenoxy]ethyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one

[0534] The title compound was obtained in the same manner in Example 1from 1-[2-(3-diethylcarbamoylbenzyl)phenoxy]acetaldehyde obtained in thesame manner in Reference Example 2 and1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one. Yield: 32%.

[0535]¹H-NMR (CDCl₃) δ (ppm); 1.02 (3H, br-s), 1.21 (3H, br-s), 1.70(2H, d, J=14 Hz), 2.66 (2H, m), 2.80-3.10 (6H, m), 3.19 (2H, br-s), 3.50(2H, br-s), 4.00 (2H, s), 4.13 (2H, m), 4.72 (2H, s), 6.80-6.95 (6H, m),7.05-7.30 (8H, m)

[0536] MS (TSP); m/z 541 (MH⁺)

Example 291-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]propyl]-4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine

[0537] The title compound was obtained in the same manner in Example 2from 1-bromo-2-[2-(4-diethylcarbamoylbenzyl)phenoxy]propane obtained inthe same manner in Reference Example 1 and4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine. Yield: 29%.

[0538]¹H-NMR (CDCl₃) δ (ppm); 1.13 (3H, br-s), 1.20 (3H, br-s), 1.25(3H, d, J=5 Hz), 1.76 (2H, m), 2.20-2.45 (4H, m), 2.52 (1H, dd, J=12 Hz,4 Hz), 2.71 (1H, dd, J=12 Hz, 7 Hz), 3.07 (2H, m), 3.25 (2H, br-s), 3.51(2H, br-s), 3.94 (1H, d, J=15 Hz), 4.04 (1H, d, J=15 Hz), 4.33 (1H, m),4.60 (1H, q, J=5 Hz), 6.80-7.00 (2H, m), 7.00-7.15 (4H, m), 7.18-7.30(6H, m), 8.91 (1H, s)

[0539] MS (TSP); m/z 541 (MH⁺)

Example 308-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]propyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one

[0540] The title compound was obtained in the same manner in Example 2from 1-bromo-2-[2-(4-diethylcarbamoylbenzyl)phenoxy]propane obtained inthe same manner in Reference Example 1 and1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one. Yield: 37%.

[0541]¹H-NMR (CDCl₃) δ (ppm); 1.10 (3H, br-s), 1.21 (3H, br-s), 1.25(3H, d, J=5 Hz), 1.65 (2H, m), 2.40-3.00 (8H, m), 3.24 (2H, br-s), 3.49(2H, br-s), 3.94 (1H, d, J=15 Hz), 4.03 (1H, d, J=15 Hz), 4.59 (1H, m),4.70 (2H, s), 6.75-6.90 (6H, m), 6.97 (1H, d, J=8 Hz), 7.09 (1H, d, J=8Hz), 7.15-7.30 (6H, m)

[0542] MS (TSP); m/z 555 (MH⁺)

Example 311-[2-[2-(4-Diisopropylcarbamoylbenzyl)phenoxy]ethyl]-4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine

[0543] The title compound was obtained in the same manner in Example 1from 1-[2-(4-diisopropylcarbamoylbenzyl)phenoxy]acetaldehyde obtained inthe same manner in Reference Example 2 and4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine. Yield: 25%.

[0544]¹H-NMR (CDCl₃) δ (ppm); 1.18 (6H, br-s), 1.45 (6H, br-s), 1.81(2H, m), 2.38 (2H, m), 2.52 (2H, m), 2.89 (2H, m), 3.20 (2H, m), 3.52(1H, m), 3.80 (1H, m), 3.99 (2H, s), 4.16 (2H, m), 4.40 (1H, m), 6.89(2H, m), 7.05 (4H, m), 7.25 (6H, m), 9.58 (1H, s)

[0545] MS (TSP); m/z 555 (MH⁺)

Example 328-[2-[2-(4-Diisopropylcarbamoylbenzyl)phenoxy]ethyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one

[0546] The title compound was obtained in the same manner in Example 1from 1-[2-(4-diisopropylcarbamoylbenzyl)phenoxy]acetaldehyde obtained inthe same manner in Reference Example 2 and1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one. Yield: 23%.

[0547]¹H-NMR (CDCl₃) δ (ppm); 1.16 (6H, br-s), 1.49 (6H, br-s), 1.71(2H, m), 2.64 (2H, m), 2.89 (4H, m), 2.97 (2H, m), 3.51 (1H, m), 3.80(1H, m), 3.99 (2H, s), 4.12 (2H, m), 4.73 (2H, s), 6.88 (6H, m),7.09-7.26 (8H, m)

[0548] MS (TSP); m/z 569 (MH⁺)

Example 331-[2-[2-[2-(4-Diethylcarbamoylphenyl)ethyl]phenoxy]ethyl]-4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine

[0549] The title compound was obtained in the same manner in Example 1from 1-[2-[2-(4-diethylcarbamoylphenyl)ethyl]phenoxy]acetaldehydeobtained in the same manner in Reference Example 2 and4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine. Yield: 30%.

[0550]¹H-NMR (CDCl₃) δ (ppm); 1.07 (3H, br-s), 1.22 (3H, br-s), 1.81(2H, m), 2.42 (4H, m), 2.94 (6H, m), 3.20 (4H, m), 3.52 (2H, br-s), 4.17(2H, t, J=5 Hz), 4.39 (1H, m), 6.88 (2H, d, J=8 Hz), 7.03 (4H, m),7.17-7.30 (6H, m), 9.86 (1H, s)

[0551] MS (TSP); m/z 541 (MH⁺)

Example 348-[2-[2-[2-(4-Diethylcarbamoylphenyl)ethyl]phenoxy]ethyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one

[0552] The title compound was obtained in the same manner in Example 1from 1-[2-[2-(4-diethylcarbamoylphenyl)ethyl]phenoxy]acetaldehydeobtained in the same manner in Reference Example 2 and1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one. Yield: 35%.

[0553]¹H-NMR (CDCl₃) δ (ppm); 1.09 (3H, br-s), 1.23 (3H, br-s), 1.71(2H, m), 2.66 (2H, m), 2.86 (10H, m), 3.23 (2H, br-s), 3.52 (2H, br-s),4.17 (2H, m), 4.70 (2H, s), 6.86 (5H, m), 7.06-7.28 (9H, m)

[0554] MS (TSP); m/z 555 (MH⁺)

Example 351-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]-4-(1,3-dihydro-3-methyl-2H-benzimidazol-2-on-1-yl)piperidine

[0555] The title compound was obtained in the same manner in Example 1from the 1-[2-(4-diethylcarbamoylbenzyl)phenoxy]acetaldehyde obtained inReference Example 2 and4-(1,3-dihydro-3-methyl-2H-benzimidazol-2-on-1-yl)piperidinetrifluoroacetate obtained in the same manner in Reference Example 3.Yield: 54%.

[0556]¹H-NMR (CDCl₃) δ (ppm); 1.10 (3H, br-s), 1.20 (3H, br-s),1.78 (2H,m),2.30-2.60 (4H, m), 2.84 (2H, t, J=5 Hz), 3.14 (2H, d, J=12 Hz), 3.24(2H, br-s), 3.41 (3H, s), 3.50 (2H, br-s), 4.00 (2H, s), 4.13 (2H, t,J=5 Hz), 4.39 (1H, m), 6.85-7.30 (12H, m)

[0557] MS (TSP); m/z 541 (MH⁺)

Example 368-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]-3-methyl-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one

[0558] The title compound was obtained in the same manner in Example 1from the 1-[2-(4-diethylcarbamoylbenzyl)phenoxy]acetaldehyde obtained inReference Example 2 and3-methyl-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one trifluoroacetateobtained in the same manner in Reference Example 3. Yield: 31%.

[0559]¹H-NMR (CDCl₃) δ (ppm); 1.10 (3H, br-s), 1.21 (3H, br-s), 1.64(2H, d, J=14 Hz), 2.70 (2H, m), 2.85-3.10 (9H, m), 3.22 (2H, br-s), 3.48(2H, br-s), 3.99 (2H, s), 4.15 (2H, m), 4.67 (2H, s), 6.80-6.95 (5H, m),7.09 (1H, d, J=8 Hz), 7.15-7.30 (7H, m)

[0560] MS (TSP); m/z 555 (MH⁺)

Example 371-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]-4-(2,3-dihydro-1H-indol-2-on-3-yl)piperidine

[0561] The title compound was obtained in the same manner in Example 1from the 1-[2-(4-diethylcarbamoylbenzyl)phenoxy]acetaldehyde obtained inReference Example 2 and 4-(2,3-dihydro-1H-indol-2-on-3-yl)piperidinehydrochloride synthesized in accordance with the descriptions of Chem.Pharm. Bull. 1983, 31, 3186. Yield: 35%.

[0562]¹H-NMR (CDCl₃) δ (ppm); 1.11 (3H, br-s), 1.23 (3H, br-s), 1.68(3H, m), 1.77 (1H, m), 2.11 (3H, m), 2.74 (2H, t, J=5 Hz), 2.94 (1H, d,J=12 Hz), 3.04 (1H, d, J=12 Hz), 3.26 (2H, br-s), 3.38 (1H, d, J=5 Hz),3.54 (2H, br-s), 3.95 (2H, s), 4.05 (2H, t, J=5 Hz), 6.85 (4H, m), 6.98(1H, t, J=8 Hz), 7.07 (1H, d, J=7 Hz), 7.15-7.26 (7H, m)

[0563] MS (FAB); m/z 526 (MH⁺)

Example 381-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]-4-(1,2,3,4-tetrahydroquinolin-1-yl)piperidine

[0564] The title compound was obtained in the same manner in Example 1from the 1-[2-(4-diethylcarbamoylbenzyl)phenoxy]acetaldehyde obtained inReference Example 2 and the4-(1,2,3,4-tetrahydroquinolin-1-yl)piperidine trifluoroacetate obtainedin Reference Example 4. Yield: 25%.

[0565]¹H-NMR (CDCl₃) δ (ppm); 1.11 (3H, br-s), 1.21 (3H, br-s), 1.74(2H, m), 1.81-1.92 (4H, m), 2.27 (2H, t, J=7 Hz), 2.72 (2H, t, J=7 Hz),2.81 (2H, t, J=5 Hz), 3.11 (2H, m), 3.20 (2H, t, J=7 Hz), 3.28 (2H,br-s), 3.52 (2H, br-s), 3.61 (1H, m), 4.00 (2H, s), 4.10 (2H, t, J=5Hz), 6.55 (1H, t, J=8 Hz), 6.65 (1H, d, J=8 Hz), 6.88 (1H, t, J=8 Hz),6.94 (1H, t, J=8 Hz), 7.04 (1H, t, J=8 Hz), 7.09 (1H, d, J=8 Hz), 7.24(6H, m)

[0566] MS (FAB); m/z 526 (MH⁺)

Example 391-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]-4-(1,2,3,4-tetrahydronaphthalen-1-yl)piperidine

[0567] The title compound was obtained in the same manner in Example 1from the 1-[2-(4-diethylcarbamoylbenzyl)phenoxy]acetaldehyde obtained inReference Example 2 and 4-(1,2,3,4-tetrahydronaphthalen-1-yl)piperidinehydrochloride synthesized in accordance with the descriptions ofJapanese Patent Laid-open Publication (Kokai) No. 11-189585. Yield: 39%.

[0568]¹H-NMR (CDCl₃) δ (ppm); 1.11 (3H, br-s), 1.22 (3H, br-s), 1.39(2H, m), 1.58 (5H, m), 1.78 (1H, m), 1.92 (1H, m), 2.05 (2H, m), 2.26(1H, m), 2.76 (4H, m), 3.01 (2H, m), 3.36 (2H, br-s), 3.51 (2H, br-s),4.01 (2H, s), 4.24 (2H, m), 6.98 (2H, m), 7.37 (10H, m)

[0569] MS (FAB); m/z 525 (MH⁺)

Example 401-[2-[2-(4-Diethylcarbamoylphenyl)phenoxy]ethyl]-4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine

[0570] The title compound was obtained in the same manner in Example 1from the 1-[2-(4-diethylcarbamoylphenyl)phenoxy]acetaldehyde obtained inReference Example 5 and4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine. Yield: 94%.

[0571]¹H-NMR (CDCl₃) δ (ppm); 1.15 (3H, br-s), 1.23 (3H, br-s), 1.77(2H, d, J=12 Hz), 2.27 (2H, t, J=12 Hz), 2.47 (2H, q, J=12 Hz), 2.82(2H, t, J=5 Hz), 3.09 (2H, d, J=12 Hz), 3.32 (2H, br-s), 3.55 (2H,br-s), 4.16 (2H, t, J=5 Hz), 4.34 (1H, m), 6.90-7.10 (4H, m), 7.25-7.55(6H, m), 7.60 (2H, d, J=8 Hz), 9.44 (1H, s)

[0572] MS (ESI); m/z 513 (MH⁺)

Example 418-[2-[2-(4-Diethylcarbamoylphenyl)phenoxy]ethyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one

[0573] The title compound was obtained in the same manner in Example 1from the 1-[2-(4-diethylcarbamoylphenyl)phenoxy]acetaldehyde obtained inReference Example 5 and 1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one.Yield: 65%.

[0574]¹H-NMR (CDCl₃) δ (ppm); 1.13 (3H, br-s), 1.23 (3H, br-s), 1.67(2H, d, J=12 Hz), 2.74 (2H, dt, J=5 Hz, 12 Hz), 2.90-3.10 (6H, m), 3.31(2H, br-s), 3.54 (2H, br-s), 4.21 (2H, t, J=5 Hz), 4.71 (2H, s),6.80-6.95 (3H, m), 7.00-7.10 (2H, m), 7.20-7.40 (7H, m), 7.59 (2H, d,J=8 Hz)

[0575] MS (ESI); m/z 527 (MH⁺)

Example 421-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]-4-(indan-1-yl)piperidine

[0576] The title compound was obtained in the same manner in Example 1from the 1-[2-(4-diethylcarbamoylbenzyl)phenoxy]acetaldehyde obtained inReference Example 2 and 4-(indan-1-yl)piperidine hydrochloridesynthesized by the method described in Japanese Patent UnexaminedPublication (Kokai) No. 11-189585. Yield: 49%.

[0577]¹H-NMR (CDCl₃) δ (ppm); 1.11 (3H, br-s), 1.22 (3H, br-s),1.32-1.56 (2H, m), 1.67 (4H, m), 1.94 (1H, m), 2.00-2.12 (2H, m), 2.76(2H, t, J=5 Hz), 2.80-2.94 (2H, m), 2.96-3.12 (3H, m), 3.26 (2H, br-s),3.53 (2H, br-s), 3.96 (2H, s), 4.09 (2H, t, J=5 Hz), 6.86 (2H, m), 7.08(1H, d, J=8 Hz), 7.12-7.27 (9H, m)

[0578] MS (FAB); m/z 511 (MH⁺)

Example 431-[2-[3-(4-Diethylcarbamoylphenyl)phenoxy]ethyl]-4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine

[0579] The title compound was obtained in the same manner in Example 1from 1-[3-(4-diethylcarbamoylphenyl)phenoxy]acetaldehyde obtained in thesame manner in Reference Example 5 and4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine. Yield: 82%.

[0580]¹H-NMR (CDCl₃) δ (ppm); 1.16 (3H, br-s), 1.26 (3H, br-s), 1.84(2H, d, J=12 Hz), 2.38 (2H, t, J=12 Hz), 2.53 (2H, q, J=12 Hz), 2.93(2H, t, J=5 Hz), 3.21 (2H, d, J=12 Hz), 3.32 (2H, br-s), 3.57 (2H,br-s), 4.22 (2H, t, J=5 Hz), 4.41 (1H, m), 6.90-7.50 (10H, m), 7.61 (2H,d, J=8 Hz), 9.92 (1H, s)

[0581] MS (ESI); m/z 513 (MH⁺)

Example 448-[2-[3-(4-Diethylcarbamoylphenyl)phenoxy]ethyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one

[0582] The title compound was obtained in the same manner in Example 1from 1-[3-(4-diethylcarbamoylphenyl)phenoxy]acetaldehyde obtained in thesame manner in Reference Example 5 and1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one. Yield: 44%.

[0583]¹H-NMR (CDCl₃) δ (ppm); 1.16 (3H, br-s), 1.26 (3H, br-s), 1.74(2H, d, J=14 Hz), 2.70 (2H, m), 2.85-3.10 (6H, m), 3.32 (2H, br-s), 3.56(2H, br-s), 4.21 (2H, t, J=5 Hz), 4.73 (2H, s), 6.80-7.00 (4H, m),7.10-7.20 (2H, m), 7.25-7.45 (6H, m), 7.61 (2H, d, J=8 Hz)

[0584] MS (ESI); m/z 527 (MH⁺)

Example 451-[2-[3-(3-Diethylcarbamoylphenyl)phenoxy]ethyl]-4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine

[0585] The title compound was obtained in the same manner in Example 1from 1-[3-(3-diethylcarbamoylphenyl)phenoxy]acetaldehyde obtained in thesame manner in Reference Example 5 and4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine. Yield: 70%.

[0586]¹H-NMR (CDCl₃) δ (ppm); 1.12 (3H, br-s), 1.27 (3H, br-s), 1.84(2H, d, J=12 Hz), 2.37 (2H, t, J=12 Hz), 2.53 (2H, q, J=12 Hz), 2.92(2H, t, J=5 Hz), 3.20 (2H, d, J=12 Hz), 3.30 (2H, br-s), 3.56 (2H,br-s), 4.21 (2H, t, J=5 Hz), 4.41 (1H, m), 6.90-7.50 (10H, m), 7.65-7.75(2H, m), 10.01 (1H, s)

[0587] MS (ESI); m/z 513 (MH⁺)

Example 468-[2-[3-(3-Diethylcarbamoylphenyl)phenoxy]ethyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one

[0588] The title compound was obtained in the same manner in Example 1from 1-[3-(3-diethylcarbamoylphenyl)phenoxy]acetaldehyde obtained in thesame manner in Reference Example 5 and1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one. Yield: 66%.

[0589]¹H-NMR (CDCl₃) δ (ppm); 1.12 (3H, br-s), 1.27 (3H, br-s), 1.74(2H, d, J=14 Hz), 2.70 (2H, m), 2.85-3.10 (6H, m), 3.29 (2H, br-s), 3.56(2H, br-s), 4.20 (2H, t, J=5 Hz), 4.72 (2H, s), 6.80-7.00 (4H, m),7.10-7.20 (3H, m), 7.25-7.50 (5H, m), 7.65-7.75 (2H, m)

[0590] MS (ESI); m/z 527 (MH⁺)

Example 471-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]-4-(1H-benzimidazol-1-yl)piperidine

[0591] The title compound was obtained in the same manner in Example 1from the 1-[2-(4-diethylcarbamoylbenzyl)phenoxy]acetaldehyde obtained inReference Example 2 and the 4-(1H-benzimidazol-1-yl)piperidinetrifluoroacetate obtained in Reference Example 6. Yield: 60%.

[0592]¹H-NMR (CDCl₃) δ (ppm); 1.09 (3H, br-s), 1.21 (3H, br-s), 2.15(4H, m), 2.34 (2H, m), 2.86 (2H, t, J=5 Hz), 3.16 (2H, m), 3.25 (2H,br-s), 3.51 (2H, br-s), 4.01 (2H, s), 4.13 (2H, t, J=5 Hz), 4.22 (1H,m), 6.90 (2H, m), 7.12 (1H, d, J=8 Hz), 7.20-7.30 (8H, m), 7.46 (1H, m),8.02 (1H, s)

[0593] MS (FAB); m/z 511 (MH⁺)

Example 481-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]-4-(1,2,3,4-tetrahydroquinolin-2-on-1-yl)piperidine

[0594] The title compound was obtained in the same manner in Example 1from the 1-[2-(4-diethylcarbamoylbenzyl)phenoxy]acetaldehyde obtained inReference Example 2 and4-(1,2,3,4-tetrahydroquinolin-2-on-1-yl)piperidine trifluoroacetateobtained in the same manner in Reference Example 6. Yield: 50%.

[0595]¹H-NMR (CDCl₃) δ (ppm); 1.10 (3H, br-s), 1.21 (3H, br-s), 1.70(2H, m), 2.29 (2H, m), 2.57 (2H, m), 2.66 (2H, m), 2.82 (4H, m), 3.11(2H, m), 3.25 (2H, br-s), 3.53 (2H, br-s), 3.99 (2H, s), 4.12 (2H, t,J=5 Hz), 4.33 (1H, m), 6.88 (2H, m), 7.00 (1H, m), 7.09 (1H, d, J=8 Hz),7.14-7.28 (8H, m)

[0596] MS (FAB); m/z 540 (MH⁺)

Example 494-Acetyl-1-[2-[2-(4-diethylcarbamoylbenzyl)phenoxy]ethyl]-4-phenylpiperidine

[0597] The title compound was obtained in the same manner in Example 1from the 1-[2-(4-diethylcarbamoylbenzyl)phenoxy]acetaldehyde obtained inReference Example 2 and 4-acetyl-4-phenylpiperidine hydrochloride.Yield: 71%.

[0598]¹H-NMR (CDCl₃) δ (ppm); 1.10 (3H, br-s), 1.19 (3H, br-s), 1.91(3H, s), 2.05 (2H, m), 2.41 (4H, m), 2.74 (2H, t, J=5 Hz), 2.80 (2H, m),3.26 (2H, br-s), 3.51 (2H, br-s), 3.97 (2H, s), 4.02 (2H, t, J=5 Hz),6.84 (1H, d, J=8 Hz), 6.88 (1H, t, J=8 Hz), 7.09 (1H, d, J=8 Hz),7.16-7.37 (10H, m)

[0599] MS (FAB); m/z 513 (MH⁺)

Example 501-[2-[2-(3-Diethylcarbamoylphenyl)phenoxy]ethyl]-4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine

[0600] The title compound was obtained in the same manner in Example 1from 1-[2-(3-diethylcarbamoylphenyl)phenoxy]acetaldehyde obtained in thesame manner in Reference Example 5 and4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine. Yield: 48%.

[0601]¹H-NMR (CDCl₃) δ (ppm); 1.13 (3H, br-s), 1.23 (3H, br-s), 1.75(2H, m), 2.24 (2H, t, J=12 Hz), 2.44 (2H, q, J=12 Hz), 2.79 (2H, t, J=5Hz), 3.05 (2H, d, J=12 Hz), 3.32 (2H, br-s), 3.55 (2H, br-s), 4.14 (2H,t, J=5 Hz), 4.33 (1H, m), 6.95-7.15 (4H, m), 7.20-7.45 (6H, m), 7.53(1H, s), 7.64 (1H, d, J=8 Hz), 9.67 (1H, s)

[0602] MS (FAB); m/z 513 (MH⁺)

Example 518-[2-[2-(3-Diethylcarbamoylphenyl)phenoxy]ethyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one

[0603] The title compound was obtained in the same manner in Example 1from 1-[2-(3-diethylcarbamoylphenyl)phenoxy]acetaldehyde obtained in thesame manner in Reference Example 5 and1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one. Yield: 62%.

[0604]¹H-NMR (CDCl₃) δ (ppm); 1.12 (3H, br-s), 1.26 (3H, br-s), 1.67(2H, m), 2.64 (2H, m), 2.75-3.00 (6H, m), 3.32 (2H, br-s), 3.54 (2H,br-s), 4.12 (2H, t, J=5 Hz), 4.72 (2H, s), 6.80-6.95 (3H, m), 7.00-7.10(2H, m), 7.20-7.40 (7H, m), 7.50 (1H, s), 7.67 (1H, d, J=8 Hz)

[0605] MS (FAB); m/z 527 (MH⁺)

Example 521-[1-[2-(4-Diethylcarbamoylbenzyl)phenoxymethyl]ethyl]-4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine

[0606] The title compound was obtained in the similar manner to that ofExample 2 from1-[2-(4-diethylcarbamoylbenzyl)phenoxymethyl]-1-methanesulfonyloxyethaneobtained in the similar manner to that of Reference Example 1 and4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine. Yield: 48%.

[0607]¹H-NMR (CDCl₃) δ (ppm); 1.00-1.30 (9H, m), 1.70-1.85 (2H, m),2.30-2.65 (4H, m), 3.00-3.15 (3H, m), 3.25 (2H, br-s), 3.49 (2H, br-s),3.90 (1H, dd, J=12 Hz, 7 Hz), 4.02 (2H, s), 4.09 (1H, dd, J=12 Hz, 5Hz), 4.34 (1H, m), 6.85-6.95 (2H, m), 7.00-7.15 (4H, m), 7.20-7.35 (6H,m), 9.34 (1H, s)

[0608] MS (APCI); m/z 541 (MH⁺)

Example 534-(1H-Benzotriazol-1-yl)-1-[2-[2-(4-diethylcarbamoylbenzyl)phenoxy]ethyl]piperidine

[0609] The title compound was obtained in the same manner in Example 1from the 1-[2-(4-diethylcarbamoylbenzyl)phenoxy]acetaldehyde obtained inReference Example 2 and 4-(1H-benzotriazol-1-yl)piperidine obtained inthe same manner in Reference Example 6. Yield: 76%.

[0610]¹H-NMR (CDCl₃) δ (ppm); 1.09 (3H, br-s), 1.20 (3H, br-s), 2.15(2H, m), 2.36-2.54 (4H, m), 2.87 (2H, t, J=5 Hz), 3.18 (2H, m), 3.25(2H, br-s), 3.51 (2H, br-s), 4.01 (2H, s), 4.14 (2H, t, J=5 Hz), 4.71(1H, m), 6.90 (2H, m), 7.12 (1H, d, J=8 Hz), 7.20-7.29 (5H, m), 7.36(1H, t, J=8 Hz), 7.46 (1H, t, J=8 Hz), 7.63 (1H, d, J=8 Hz), 8.06 (1H,d, J=8 Hz)

[0611] MS (FAB); m/z 512 (MH⁺)

Example 541-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]-4-(2,3-dihydro-1H-indol-1-yl)piperidine

[0612] The title compound was obtained in the same manner in Example 1from the 1-[2-(4-diethylcarbamoylbenzyl)phenoxy]acetaldehyde obtained inReference Example 2 and 4-(2,3-dihydro-1H-indol-1-yl)piperidine in thesame manner in Reference Example 4. Yield: 47%.

[0613]¹H-NMR (CDCl₃) δ (ppm); 1.11 (3H, br-s), 1.21 (3H, br-s), 1.83(4H, m), 2.36 (2H, m), 2.94 (4H, m), 3.25 (2H, br-s), 3.36 (2H, t, J=5Hz), 3.51 (4H, m), 3.99 (2H, s), 4.12 (2H, m), 4.18 (1H, m), 6.46 (1H,d, J=8 Hz), 6.61 (1H, t, J=8 Hz), 6.87 (1H, d, J=8 Hz), 6.93 (1H, t, J=8Hz), 7.04 (2H, m), 7.12 (1H, d, J=8 Hz), 7.18-7.28 (5H, m)

[0614] MS (TSP); m/z 512 (MH⁺)

Example 558-[1-[2-(4-Diethylcarbamoylbenzyl)phenoxymethyl]ethyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one

[0615] The title compound was obtained in a manner similar to that ofExample 2 from1-[2-(4-diethylcarbamoylbenzyl)phenoxymethyl]-1-methanesulfonyloxyethaneobtained in the similar manner to that of Reference Example 1 and1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one. Yield: 12%.

[0616]¹H-NMR (CDCl₃) δ (ppm); 1.00-1.30 (9H, m), 1.67 (2H, d, J=14 Hz),2.63 (2H, m), 2.79 (2H, m), 3.05-3.30 (5H, m), 3.50 (2H, br-s),3.80-4.15 (4H, m), 4.71 (2H, s), 6.70-7.00 (6H, m), 7.05-7.30 (8H, m)

[0617] MS (TSP); m/z 555 (MH⁺)

Example 564-(1H-Benzimidazol-1-yl)-1-[1-[2-(4-diethylcarbamoylbenzyl)phenoxymethyl]ethyl]piperidine

[0618] The title compound was obtained in the similar manner to that ofExample 2 from1-[2-(4-diethylcarbamoylbenzyl)phenoxymethyl]-1-methanesulfonyloxyethaneobtained in the similar manner to that of Reference Example 1 and4-(1H-benzimidazol-1-yl)piperidine trifluoroacetate. Yield: 27%.

[0619]¹H-NMR (CDCl₃) δ (ppm); 1.00-1.30 (9H, m), 2.14 (4H, m), 2.55 (2H,m), 3.07 (3H, m), 3.23 (2H, br-s), 3.50 (2H, br-s), 3.85-4.25 (5H, m),6.85-6.95 (2H, m), 7.10-7.35 (8H, m), 7.44 (1H, m), 7.80 (1H, m), 8.01(1H, s)

[0620] MS (ESI); m/z 525 (MH⁺)

Example 571-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]-4-(6-fluoro-1,2-benzisothiazol-3-yl)piperidine

[0621] The title compound was obtained in the same manner in Example 1from the 1-[2-(4-diethylcarbamoylbenzyl)phenoxy]acetaldehyde obtained inReference Example 2 and 4-(6-fluoro-1,2-benzisothiazol-3-yl)piperidinesynthesized in accordance with the descriptions of WO98/42710. Yield:12%.

[0622]¹H-NMR (CDCl₃) δ (ppm); 1.10 (3H, br-s), 1.21 (3H, br-s), 2.01(2H, m), 2.11 (2H, m), 2.33 (2H, m), 2.77 (2H, t, J=5 Hz), 3.14 (2H, m),3.20 (1H, m), 3.25 (2H, br-s), 3.51 (2H, br-s), 4.00 (2H, s), 4.14 (2H,t, J=5 Hz), 6.89 (2H, m), 7.09-7.29 (7H, m), 7.57 (1H, m), 7.96 (1H, m)

[0623] MS (TSP); m/z 546 (MH⁺)

Example 581-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine

[0624] The title compound was obtained in the same manner in Example 1from the 1-[2-(4-diethylcarbamoylbenzyl)phenoxy]acetaldehyde obtained inReference Example 2 and 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidinesynthesized in accordance with the descriptions of EP428437. Yield: 31%.

[0625]¹H-NMR (CDCl₃) δ (ppm); 1.09 (3H, br-s), 1.21 (3H, br-s), 2.06(4H, m), 2.34 (2H, m), 2.86 (2H, t, J=5 Hz), 3.08 (1H, m), 3.14 (2H, m),3.25 (2H, br-s), 3.52 (2H, br-s), 4.00 (2H, s), 4.15 (2H, t, J=5 Hz),6.90 (2H, m), 7.04-7.13 (2H, m), 7.19-7.29 (6H, m), 7.71 (1H, m)

[0626] MS (TSP); m/z 530 (MH⁺)

Example 591-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]-4-(1H-indol-3-yl)piperidine

[0627] The title compound was obtained in the same manner in Example 1from the 1-[2-(4-diethylcarbamoylbenzyl)phenoxy]acetaldehyde obtained inReference Example 2 and 4-(1H-indol-3-yl)piperidine hydrochloridesynthesized in accordance with the descriptions of J. Org. Chem., 1975,40, 2525 and Helv. Chim. Acta, 1968, 51, 260. Yield: 30%.

[0628]¹H-NMR (CDCl₃) δ (ppm); 1.08 (3H, br-s), 1.21 (3H, br-s), 1.85(2H, m), 2.06 (2H, m), 2.34 (2H, m), 2.86 (2H, t, J=5 Hz), 3.13 (2H, m),3.24 (2H, br-s), 3.52 (2H, br-s), 4.01 (2H, s), 4.10 (1H, m), 4.16 (2H,t, J=5 Hz), 6.89 (1H, d, J=8 Hz), 6.93 (1H, m), 7.07-7.29 (9H, m), 7.35(1H, d, J=8 Hz), 7.64 (1H, d, J=8 Hz), 8.14 (1H, s)

[0629] MS (TSP); m/z 510 (MH⁺)

Example 601′-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]-2,3-dihydrospiro[1H-indene-1,4′-piperidine]

[0630] The title compound was obtained in the same manner in Example 1from the 1-[2-(4-diethylcarbamoylbenzyl)phenoxy]acetaldehyde obtained inReference Example 2 and 2,3-dihydrospiro[1H-indene-1,4′-piperidine]synthesized in accordance with the descriptions of J. Med. Chem. 1992,35, 2033. Yield: 49%.

[0631]¹H-NMR (CDCl₃) δ (ppm); 1.09 (3H, br-s), 1.20 (3H, br-s), 1.55(2H, m), 1.95 (2H, m), 2.02 (2H, t, J=7 Hz), 2.35 (2H, m), 2.85 (2H, t,J=5 Hz), 2.90 (2H, t, J=7 Hz), 2.98 (2H, m), 3.25 (2H, br-s), 3.51 (2H,br-s), 4.00 (2H, s), 4.16 (2H, t, J=5 Hz), 6.90 (1H, d, J=8 Hz), 7.10(1H, d, J=8 Hz), 7.16-7.28 (10H, m)

[0632] MS (TSP); m/z 497 (MH⁺)

Example 61(R)-1-[1-[2-(4-Diethylcarbamoylbenzyl)phenoxymethyl]ethyl]-4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine

[0633] The title compound was obtained in the similar manner to that ofExample 2 from(S)-1-[2-(4-diethylcarbamoylbenzyl)phenoxymethyl]-1-methanesulfonyloxyethaneobtained in the similar manner to that of Reference Example 1 and4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine. Yield: 68%.

[0634]¹H-NMR (CDCl₃) δ (ppm); 1.00-1.30 (9H, m), 1.80-1.90 (2H, m),2.30-2.65 (4H, m), 3.00-3.15 (3H, m), 3.25 (2H, br-s), 3.49 (2H, br-s),3.90 (1H, dd, J=12 Hz, 7 Hz), 4.02 (2H, s), 4.09 (1H, dd, J=12 Hz, 5Hz), 4.34 (1H, m), 6.85-6.95 (2H, m), 7.00-7.15 (4H, m), 7.20-7.35 (6H,m), 9.78 (1H, s)

[0635] MS (TSP); m/z 541 (MH⁺)

[0636] [a]_(D) ²²+3.3° (c 1.02, CH₂Cl₂)

Example 62(S)-1-[1-[2-(4-Diethylcarbamoylbenzyl)phenoxymethyl]ethyl]-4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine

[0637] The title compound was obtained in the similar manner to that ofExample 2 from(R)-1-bromo-1-[2-(4-diethylcarbamoylbenzyl)phenoxymethyl]ethane obtainedin the similar manner to that of Reference Example 1 and4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine. Yield: 69%.

[0638]¹H-NMR (CDCl₃) δ (ppm); 1.00-1.30 (9H, m), 1.80-1.90 (2H, m),2.30-2.65 (4H, m), 3.00-3.15 (3H, m), 3.25 (2H, br-s), 3.49 (2H, br-s),3.90 (1H, dd, J=12 Hz, 7 Hz), 4.02 (2H, s), 4.09 (1H, dd, J=12 Hz, 5Hz), 4.34 (1H, m), 6.85-6.95 (2H, m), 7.00-7.15 (4H, m), 7.20-7.35 (6H,m), 9.74 (1H, s)

[0639] MS (TSP); m/z 541 (MH⁺)

Example 631-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]-4-(1,2,3,4-tetrahydroquinazolin-2-on-1-yl)piperidine

[0640] The title compound was obtained in the same manner in Example 1from the 1-[2-(4-diethylcarbamoylbenzyl)phenoxy]acetaldehyde obtained inReference Example 2 and the4-(1,2,3,4-tetrahydroquinazolin-2-on-1-yl)piperidine trifluoroacetateobtained in Reference Example 7. Yield: 26%.

[0641]¹H-NMR (CDCl₃) δ (ppm); 1.10 (3H, br-s), 1.21 (3H, br-s), 1.78(2H, m), 2.31 (2H, m), 2.74 (2H, m), 2.85 (2H, t, J=5 Hz), 3.13 (2H, m),3.26 (2H, br-s), 3.52 (2H, br-s), 3.99 (2H, s), 4.09 (1H, m), 4.13 (2H,t, J=5 Hz), 4.27 (2H, s), 5.13 (1H, m), 6.89 (2H, m), 6.98 (1H, t, J=8Hz), 7.08 (2H, m), 7.14 (1H, d, J=8 Hz), 7.19-7.29 (6H, m)

[0642] MS (TSP); m/z 541 (MH⁺)

Example 641′-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]-2,3-dihydrospiro-[isoquinoline-4(1H),4′-piperidin]-1-one

[0643] The title compound was obtained in the same manner in Example 1from the 1-[2-(4-diethylcarbamoylbenzyl)phenoxy]acetaldehyde obtained inReference Example 2 and2,3-dihydrospiro[isoquinoline-4(1H),4′-piperidin]-1-one synthesized inaccordance with the descriptions of WO94/13696. Yield: 74%.

[0644]¹H-NMR (CDCl₃) δ (ppm); 1.09 (3H, br-s), 1.22 (3H, br-s), 1.78(2H, m), 2.07 (2H, m), 2.25 (2H, m), 2.79 (2H, t, J=5 Hz), 2.87 (2H, m),3.24 (2H, br-s), 3.49 (2H, s), 3.54 (2H, br-s), 4.00 (2H, s), 4.11 (2H,t, J=5 Hz), 6.71 (1H, s), 6.86 (1H, d, J=8 Hz), 6.91 (1H, t, J=8 Hz),7.14 (1H, d, J=8 Hz), 7.20 (3H, m), 7.27 (2H, m), 7.35 (1H, t, J=8 Hz),7.43 (1H, d, J=8 Hz), 7.51 (1H, t, J=8 Hz), 8.09 (1H, d, J=8 Hz)

[0645] MS (TSP); m/z 526 (MH⁺)

Example 651-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]spiro[piperidine-4,4′(1′H)-quinolin]-2′(3′H)-one

[0646] The title compound was obtained in the same manner in Example 1from the 1-[2-(4-diethylcarbamoylbenzyl)phenoxy]acetaldehyde obtained inReference Example 2 and spiro[piperidine-4,4′(1′H)-quinolin]-2′(3′H)-onesynthesized in accordance with the descriptions of WO94/13696. Yield:51%.

[0647]¹H-NMR (CDCl₃) δ (ppm); 1.09 (3H, br-s), 1.21 (3H, br-s), 1.70(2H, m), 2.06 (2H, m), 2.51 (2H, m), 2.69 (2H, s), 2.88 (4H, m), 3.26(2H, br-s), 3.52 (2H, br-s), 3.99 (2H, s), 4.12 (2H, t, J=5 Hz), 6.77(1H, d, J=8 Hz), 6.89 (2H, m), 7.08 (2H, m), 7.18-7.28 (7H, m), 7.37(1H, d, J=8 Hz)

[0648] MS (TSP); m/z 526 (MH⁺)

Example 661′-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]Spiro[1H-indene-1,4′-piperidin]-3(2H)-one

[0649] The title compound was obtained in the same manner in Example 1from the 1-[2-(4-diethylcarbamoylbenzyl)phenoxy]acetaldehyde obtained inReference Example 2 and spiro[1H-indene-1,4′-piperidin]-3(2H)-onesynthesized in accordance with the descriptions of WO94/13696. Yield:50%.

[0650]¹H-NMR (CDCl₃) δ (ppm); 1.09 (3H, br-s), 1.21 (3H, br-s), 1.52(2H, m), 2.15 (2H, m), 2.26 (2H, m), 2.59 (2H, s), 2.86 (2H, t, J=5 Hz),3.07 (2H, m), 3.25 (2H, br-s), 3.50 (2H, br-s), 4.00 (2H, s), 4.15 (2H,t, J=5 Hz), 6.90 (2H, m), 7.11 (1H, d, J=8 Hz), 7.19-7.28 (5H, m), 7.40(1H, t, J=8 Hz), 7.55 (1H, d, J=8 Hz), 7.64 (1H, t, J=8 Hz), 7.73 (1H,d, J=8 Hz)

[0651] MS (TSP); m/z 511 (MH⁺)

Example 671-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]-4-(3,3-dimethyl-2,3-dihydro-1H-indol-2-on-1-yl)piperidine

[0652] The title compound was obtained in the same manner in Example 1from the 1-[2-(4-diethylcarbamoylbenzyl)phenoxy]acetaldehyde obtained inReference Example 2 and4-(3,3-dimethyl-2,3-dihydro-1H-indol-2-on-1-yl)piperidinetrifluoroacetate obtained in the same manner in Reference Example 6.Yield: 78%.

[0653]¹H-NMR (CDCl₃) δ (ppm); 1.10 (3H, br-s), 1.22 (3H, br-s), 1.35(6H, s), 1.69 (2H, m), 2.30 (2H, m), 2.46 (2H, m), 2.83 (2H, t, J=5 Hz),3.12 (2H, m), 3.26 (2H, br-s), 3.52 (2H, br-s), 4.00 (2H, s), 4.12 (2H,t, J=5 Hz), 4.33 (1H, m), 6.90 (2H, m), 7.03 (1H, t, J=8 Hz), 7.10 (1H,d, J=8 Hz), 7.18-7.28 (8H, m)

[0654] MS (TSP); m/z 554 (MH⁺)

Example 681-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]-4-phenylpiperidine

[0655] The title compound was obtained in the same manner in Example 1from the 1-[2-(4-diethylcarbamoylbenzyl)phenoxy]acetaldehyde obtained inReference Example 2 and the 4-phenylpiperidine hydrochloride obtained inReference Example 8. Yield: 58%.

[0656]¹H-NMR (CDCl₃) δ (ppm); 1.10 (3H, br-s), 1.21 (3H, br-s), 1.82(4H, m), 2.24 (2H, m), 2.50 (1H, m), 2.83 (2H, t, J=5 Hz), 3.11 (2H, m),3.26 (2H, br-s), 3.52 (2H, br-s), 4.00 (2H, s), 4.13 (2H, t, J=5 Hz),6.84-6.96 (3H, m), 7.10 (1H, d, J=8 Hz), 7.16-7.32 (9H, m)

[0657] MS (TSP); m/z 471 (MH⁺)

Example 691-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]-4-(1H-indol-1-yl)piperidine

[0658] The title compound was obtained in the same manner in Example 1from the 1-[2-(4-diethylcarbamoylbenzyl)phenoxy]acetaldehyde obtained inReference Example 2 and 4-(1H-indol-1-yl)piperidine hydrochloridesynthesized in accordance with the descriptions of Syn. Commun. 1988,18, 265. Yield: 76%.

[0659]¹H-NMR (CDCl₃) δ (ppm); 1.09 (3H, br-s), 1.20 (3H, br-s), 2.08(4H, m), 2.36 (2H, m), 2.86 (2H, t, J=5 Hz), 3.16 (2H, d, J=12 Hz), 3.23(2H, br-s), 3.51 (2H, br-s), 4.00 (2H, s), 4.13 (2H, t, J=5 Hz), 4.25(1H, m), 6.51 (1H, d, J=3 Hz), 6.80-7.00 (2H, m), 7.10 (2H, m),7.15-7.30 (7H, m), 7.38 (1H, d, J=8 Hz), 7.62 (1H, d, J=8 Hz)

[0660] MS (TSP); m/z 510 (MH⁺)

Example 701′-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]spiro[3H-indole-3,4′-piperidin]-2(1H)-one

[0661] The title compound was obtained in the same manner in Example 1from the 1-[2-(4-diethylcarbamoylbenzyl)phenoxy]acetaldehyde obtained inReference Example 2 and the spiro[3H-indole-3,4′-piperidine]-2(1H)-onehydrochloride obtained in Reference Example 9. Yield: 50%.

[0662]¹H-NMR (CDCl₃) δ (ppm); 1.10 (3H, br-s), 1.20 (3H, br-s), 1.94(4H, m), 2.85 (2H, m), 2.96 (2H, t, J=5 Hz), 3.08 (2H, m), 3.26 (2H,br-s), 3.50 (2H, br-s), 4.00 (2H, s), 4.18 (2H, t, J=5 Hz), 6.80-6.90(3H, m), 7.00-7.15 (2H, m), 7.15-7.30 (6H, m), 7.35 (1H, d, J=8 Hz),7.77 (1H, br-s)

[0663] MS (TSP); m/z 512 (MH⁺)

Example 711′-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]spiro[1H-indene-1,4°-piperidine]

[0664] The title compound was obtained in the same manner in Example 1from the 1-[2-(4-diethylcarbamoylbenzyl)phenoxy]acetaldehyde obtained inReference Example 2 and spiro[1H-indene-1,4′-piperidine] synthesized inaccordance with the descriptions of J. Med. Chem., 1992, 35, 2033.Yield: 59%.

[0665]¹H-NMR (CDCl₃) δ (ppm); 1.09 (3H, br-s), 1.20 (3H, br-s), 1.35(2H, d, J=12 Hz), 2.20 (2H, td, J=12 Hz, 3 Hz), 2.52 (2H, t, J=12 Hz),2.92 (2H, t, J=5 Hz), 3.09 (2H, d, J=12 Hz), 3.23 (2H, br-s), 3.50 (2H,br-s), 4.00 (2H, s), 4.18 (2H, t, J=5 Hz), 6.75 (1H, d, J=6 Hz),6.80-6.95 (3H, m), 7.05-7.40 (10H, m)

[0666] MS (TSP); m/z 495 (MH⁺)

Example 721-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]-4-(2-methyl-1H-benzimidazol-1-yl)piperidine

[0667] The title compound was obtained in the same manner in Example 1from the 1-[2-(4-diethylcarbamoylbenzyl)phenoxy]acetaldehyde obtained inReference Example 2 and 4-(2-methyl-1H-benzimidazol-1-yl)piperidinetrifluoroacetate obtained in the same manner in Reference Example 6.Yield: 28%.

[0668]¹H-NMR (CDCl₃) δ (ppm); 1.08 (3H, br-s), 1.20 (3H, br-s), 1.84(2H, m), 2.30 (2H, m), 2.65 (3H, s), 2.75 (2H, m), 2.86 (2H, t, J=5 Hz),3.17 (2H, m), 3.24 (2H, br-s), 3.50 (2H, br-s), 4.01 (2H, s), 4.15 (2H,t, J=5 Hz), 4.18 (1H, m), 6.91 (2H, m), 7.11-7.27 (8H, m), 7.58 (1H, m),7.68 (1H, m)

[0669] MS (TSP); m/z 525 (MH⁺)

Example 731-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]-4-(3,4-dihydro-2H-1,4-benzoxazin-3-on-4-yl)piperidine

[0670] The title compound was obtained in the same manner in Example 1from the 1-[2-(4-diethylcarbamoylbenzyl)phenoxy]acetaldehyde obtained inReference Example 2 and the4-(3,4-dihydro-2H-1,4-benzoxazin-3-on-4-yl)piperidine trifluoroacetateobtained in Reference Example 10. Yield: 66%.

[0671]¹H-NMR (CDCl₃) δ (ppm); 1.10 (3H, br-s), 1.21 (3H, br-s), 1.74(2H, m), 2.28 (2H, m), 2.65 (2H, m), 2.82 (2H, t, J=5 Hz), 3.12 (2H, m),3.26 (2H, br-s), 3.53 (2H, br-s), 3.99 (2H, s), 4.11 (2H, t, J=5 Hz),4.37 (1H, m), 4.50 (2H, s), 6.88 (2H, m), 7.00 (2H, s), 7.10 (1H, d, J=8Hz), 7.17-7.28 (7H, m)

[0672] MS (FAB); m/z 542 (MH⁺)

Example 741-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]-4-(1H-imidazol-1-yl)piperidine

[0673] The title compound was obtained in the same manner in Example 2from 1-bromo-2-[2-(4-diethylcarbamoylbenzyl)phenoxy]ethane obtained inthe same manner in Reference Example 1 and4-(1H-imidazol-1-yl)piperidine trifluoroacetate obtained in the samemanner in Reference Example 6. Yield: 53%.

[0674]¹H-NMR (CDCl₃) δ (ppm); 1.10 (3H, br-s), 1.22 (3H, br-s), 1.99(4H, m), 2.11 (2H, m), 2.82 (2H, t, J=5 Hz), 3.05 (2H, m), 3.28 (2H,br-s), 3.52 (2H, br-s), 3.92 (1H, m), 3.99 (2H, s), 4.09 (2H, t, J=5Hz), 6.86 (1H, d, J=8 Hz), 6.91 (2H, t, J=8 Hz), 6.99 (1H, s), 7.05 (1H,s), 7.11 (1H, d, J=8 Hz), 7.24 (4H, m), 7.57 (1H, s)

[0675] MS (EI); m/z 554 (M⁺)

Example 751-[1-[2-(4-Diethylcarbamoylbenzyl)phenoxymethyl]propyl]-4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine

[0676] The title compound was obtained in the similar manner to that ofExample 2 from1-[2-(4-diethylcarbamoylbenzyl)phenoxymethyl]-1-methanesulfonyloxypropaneobtained in the similar manner to that of Reference Example 1 and4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine. Yield: 32%.

[0677]¹H-NMR (CDCl₃) δ (ppm); 0.98 (3H, t, J=7 Hz), 1.10 (3H, br-s),1.18 (3H, br-s), 1.58 (2H, m), 1.85 (2H, d, J=12 Hz), 2.30-2.60 (3H, m),2.80 (2H, m), 3.03 (2H, m), 3.25 (2H, br-s), 3.50 (2H, br-s), 3.90-4.15(4H, m), 4.32 (1H, m), 6.91 (2H, m), 7.00-7.15 (4H, m), 7.20-7.35 (6H,m), 9.92 (1H, s)

[0678] MS (TSP); m/z 555 (MH⁺)

Example 768-[1-[2-(4-Diethylcarbamoylbenzyl)phenoxymethyl]propyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one

[0679] The title compound was obtained in the similar manner to that ofExample 2 from1-[2-(4-diethylcarbamoylbenzyl)phenoxymethyl]-1-methanesulfonyloxypropaneobtained in the similar manner to that of Reference Example 1 and1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one. Yield: 19%.

[0680]¹H-NMR (CDCl₃) δ (ppm); 0.98 (3H, t, J=7 Hz), 1.10 (3H, br-s),1.19 (3H, br-s), 1.50-1.75 (4H, m), 2.50-2.90 (6H, m), 3.00-3.10 (1H,m), 3.20-3.40 (4H, m), 3.50 (2H, br-s), 3.96 (1H, m), 4.02 (2H, s), 4.10(1H, m), 6.80-6.95 (5H, m), 7.08 (1H, d, J=8 Hz), 7.15-7.30 (8H, m)

[0681] MS (TSP); m/z 569 (MH⁺)

Example 771′-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]spiro[isobenzofuran-1(3H),4′-piperidin]-3-one

[0682] The title compound was obtained in the same manner in Example 1from the 1-[2-(4-diethylcarbamoylbenzyl)phenoxy]acetaldehyde obtained inReference Example 2 and spiro[isobenzofuran-1(3H),4′-piperidin]-3-onehydrochloride synthesized in accordance with the descriptions of J. Org.Chem., 1976, 41, 2628. Yield: 44%.

[0683]¹H-NMR (CDCl₃) δ (ppm); 1.10 (3H, br-s), 1.20 (3H, br-s), 1.72(2H, m), 2.23 (2H, m), 2.71 (2H, m), 2.91 (2H, m), 3.02 (2H, m), 3.26(2H, br-s), 3.51 (2H, br-s), 4.00 (2H, s), 4.14 (2H, m), 6.89 (2H, m),7.11 (1H, d, J=8 Hz), 7.19-7.28 (5H, m), 7.41 (1H, d, J=8 Hz), 7.53 (1H,t, J=8 Hz), 7.67 (1H, t, J=8 Hz), 7.88 (1H, d, J=8 Hz)

[0684] MS (FAB); m/z 513 (MH⁺)

Example 781-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]-4-(6-fluoro-1H-indol-3-yl)piperidine

[0685] The title compound was obtained in the same manner in Example 1from the 1-[2-(4-diethylcarbamoylbenzyl)phenoxy]acetaldehyde obtained inReference Example 2 and 4-(6-fluoro-1H-indol-3-yl)piperidinehydrochloride obtained in the same manner in J. Org. Chem., 1975, 40,2525 and Helv. Chim. Acta, 1968, 51, 260. Yield: 44%.

[0686]¹H-NMR (CDCl₃) δ (ppm); 1.09 (3H, br-s), 1.21 (3H, br-s), 1.81(2H, m), 2.02 (2H, m), 2.31 (2H, m), 2.85 (2H, t, J=5 Hz), 3.10 (2H, m),3.25 (2H, br-s), 3.52 (2H, br-s), 4.01 (2H, s), 4.10 (1H, m), 4.14 (2H,t, J=5 Hz), 6.86 (4H, m), 7.01 (1H, d, J=8 Hz), 7.10 (1H, d, J=8 Hz),7.22 (6H, m), 7.53 (1H, m)

[0687] MS (TSP); m/z 528 (MH⁺)

Example 791-[2-[2-(4-Diethylcarbamoylbenzyl)-4-methoxyphenoxy]ethyl]-4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine

[0688] The title compound was obtained in the same manner in Example 1from 1-[2-(4-diethylcarbamoylbenzyl)-4-methoxyphenoxy]acetaldehydeobtained in the same manner in Reference Example 2 and4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine. Yield: 80%.

[0689]¹H-NMR (CDCl₃) δ (ppm); 1.10 (3H, br-s), 1.20 (3H, br-s), 1.81(2H, d, J=12 Hz), 2.33 (2H, t, J=12 Hz), 2.49 (2H, q, J=12 Hz), 2.82(2H, t, J=5 Hz), 3.15 (2H, d, J=12 Hz), 3.24 (2H, br-s), 3.50 (2H,br-s), 3.74 (3H, s), 3.99 (2H, s), 4.08 (2H, t, J=5 Hz), 4.38 (1H, m),6.65-6.80 (2H, m), 6.83 (1H, d, J=8 Hz), 7.00-7.15 (3H, m), 7.20-7.35(5H, m), 9.84 (1H, s)

[0690] MS (TSP); m/z 557 (MH⁺)

Example 808-[2-[2-(4-Diethylcarbamoylbenzyl)-4-methoxyphenoxy]ethyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one

[0691] The title compound was obtained in the same manner in Example 1from 1-[2-(4-diethylcarbamoylbenzyl)-4-methoxyphenoxy]acetaldehydeobtained in the same manner in Reference Example 2 and1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one. Yield: 67%.

[0692]¹H-NMR (CDCl₃) δ (ppm); 1.10 (3H, br-s), 1.21 (3H, br-s), 1.70(2H, d, J=12 Hz), 2.67 (2H, m), 2.80-3.05 (6H, m), 3.25 (2H, br-s), 3.49(2H, br-s), 3.73 (3H, s), 3.98 (2H, s), 4.08 (2H, t, J=5 Hz), 4.72 (2H,s), 6.65-6.75 (2H, m), 6.80-6.95 (4H, m), 7.01 (1H, s), 7.20-7.30 (6H,m)

[0693] MS (TSP); m/z 571 (MH⁺)

Example 811-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]-4-(1,3-dihydro-7-methyl-2H-benzimidazol-2-on-1-yl)piperidine

[0694] The title compound was obtained in the same manner in Example 1from the 1-[2-(4-diethylcarbamoylbenzyl)phenoxy]acetaldehyde obtained inReference Example 2 and the4-(1,3-dihydro-7-methyl-2H-benzimidazol-2-on-1-yl)piperidinehydrobromide obtained in Reference Example 11. Yield: 15%.

[0695]¹H-NMR (CDCl₃) δ (ppm); 1.10 (3H, br-s), 1.20 (3H, br-s), 1.78(2H, m), 2.24 (2H, m), 2.59 (3H, s), 2.88 (4H, m), 3.16 (2H, m), 3.26(2H, br-s), 3.51 (2H, br-s), 4.00 (2H, s), 4.14 (2H, m), 4.38 (1H, m),6.80 (1H, m), 6.90 (5H, m), 7.09 (1H, d, J=8 Hz), 7.19-7.29 (4H, m),9.86 (1H, s)

[0696] MS (EI); m/z 540 (M⁺)

Example 821-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]-4-(5-fluoro-1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine

[0697] The title compound was obtained in the same manner in Example 1from the 1-[2-(4-diethylcarbamoylbenzyl)phenoxy]acetaldehyde obtained inReference Example 2 and the4-(5-fluoro-1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidinehydrobromide obtained in the same manner in Reference Example 11. Yield:18%.

[0698]¹H-NMR (CDCl₃) δ (ppm); 1.09 (3H, br-s), 1.20 (3H, br-s), 1.80(2H, m), 2.32 (2H, m), 2.42 (2H, m), 2.84 (2H, t, J=5 Hz), 3.14 (2H, m),3.25 (2H, br-s), 3.52 (2H, br-s), 4.00 (2H, s), 4.12 (2H, t, J=5 Hz),4.34 (1H, m), 6.76 (1H, m), 6.83 (1H, m), 6.90 (2H, m), 7.10 (1H, d, J=8Hz), 7.14-7.24 (6H, m), 9.82 (1H, s)

[0699] MS (FAB); m/z 545 (MH⁺)

Example 831′-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]-2,3-dihydro-5-methylspiro[isoquinoline-4(1H),4′-piperidin]-1-one

[0700] The title compound was obtained in the same manner in Example 1from the 1-[2-(4-diethylcarbamoylbenzyl)phenoxy]acetaldehyde obtained inReference Example 2 and the2,3-dihydro-5-methylspiro[isoquinoline-4(1H),4′-piperidin]-1-oneobtained in Reference Example 12. Yield: 56%.

[0701]¹H-NMR (CDCl₃) δ (ppm); 1.10 (3H, br-s), 1.23 (3H, br-s), 1.69(2H, d, J=14 Hz), 2.25 (2H, t, J=14 Hz), 2.56 (2H, m), 2.63 (3H, s),2.75 (2H, t, J=5 Hz), 2.85 (2H, d, J=14 Hz), 3.25 (2H, br-s), 3.50 (4H,m), 3.99 (2H, s), 4.12 (2H, t, J=5 Hz), 6.64 (1H, s), 6.85-6.95 (2H, m),7.12 (1H, d, J=8 Hz), 7.15-7.30 (7H, m), 8.02 (1H, d, J=8 Hz)

[0702] MS (FAB); m/z 540 (MH⁺)

Example 841-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]-4-(2-hydroxymethyl-1H-benzimidazol-1-yl)piperidine

[0703] The title compound was obtained in the same manner in Example 1from the 1-[2-(4-diethylcarbamoylbenzyl)phenoxy]acetaldehyde obtained inReference Example 2 and4-(2-hydroxymethyl-1H-benzimidazol-1-yl)piperidine obtained in the samemanner in Reference Example 6. Yield: 12%.

[0704]¹H-NMR (CDCl₃) δ (ppm); 1.06 (3H, br-s), 1.15 (3H, br-s), 1.76(2H, m), 2.18 (2H, m), 2.48 (2H, m), 2.89 (2H, m), 3.01 (2H, m), 3.20(2H, br-s), 3.45 (2H, br-s), 4.03 (2H, s), 4.15 (2H, m), 4.48 (1H, m),4.91 (2H, s), 6.89 (1H, m), 6.95 (1H, m), 7.19-7.26 (8H, m), 7.62 (1H,m), 7.71 (1H, m)

[0705] MS (TSP); m/z 541 (MH⁺)

Example 851-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]-4-[2-(2-hydroxyethyl)-1H-benzimidazol-1-yl]piperidine

[0706] The title compound was obtained in the same manner in Example 1from the 1-[2-(4-diethylcarbamoylbenzyl)phenoxy]acetaldehyde obtained inReference Example 2 and4-[2-(2-hydroxyethyl)-1H-benzimidazol-1-yl]piperidine trifluoroacetateobtained in the same manner in Reference Example 6. Yield: 25%.

[0707]¹H-NMR (CDCl₃) δ (ppm); 1.00 (3H, br-s), 1.15 (3H, br-s), 1.84(2H, m), 2.40 (2H, m), 2.60 (2H, m), 2.90 (2H, t, J=5 Hz), 3.16 (2H, t,J=7 Hz), 3.21 (4H, m), 3.44 (2H, br-s), 3.96 (2H, t, J=7 Hz), 4.06 (2H,s), 4.19 (2H, t, J=5 Hz), 4.50 (1H, m), 6.92 (1H, t, J=8 Hz), 7.00 (1H,d, J=8 Hz), 7.15-7.26 (8H, m), 7.56 (1H, m), 7.78 (1H, m)

[0708] MS (TSP); m/z 555 (MH⁺)

Example 861-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]-4-(2-hydroxymethyl-7-methyl-1H-benzimidazol-1-yl)piperidine

[0709] The title compound was obtained in the same manner in Example 1from the 1-[2-(4-diethylcarbamoylbenzyl)phenoxy]acetaldehyde obtained inReference Example 2 and the4-(2-hydroxymethyl-7-methyl-1H-benzimidazol-1-yl)piperidine obtained inReference Example 13. Yield: 44%.

[0710]¹H-NMR (CDCl₃) δ (ppm); 1.06 (3H, br-s), 1.16 (3H, br-s), 1.73(2H, m), 2.17 (2H, m), 2.46 (2H, m), 2.62 (3H, s), 2.86 (2H, m), 2.99(2H, m), 3.20 (2H, br-s), 3.46 (2H, br-s), 4.03 (2H, s), 4.13 (2H, m),4.45 (1H, m), 4.94 (2H, s), 6.89 (1H, m), 6.94 (1H, m), 7.01 (1H, m),7.07-7.26 (7H, m), 7.44 (1H, m)

[0711] MS (TSP); m/z 555 (MH⁺)

Example 871-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]-4-(2-hydroxymethyl-7-methoxy-1H-benzimidazol-1-yl)piperidine

[0712] The title compound was obtained in the same manner in Example 1from the 1-[2-(4-diethylcarbamoylbenzyl)phenoxy]acetaldehyde obtained inReference Example 2 and4-(2-hydroxymethyl-7-methoxy-1H-benzimidazol-1-yl)piperidine obtained inthe same manner in Reference Example 13. Yield: 39%.

[0713]¹H-NMR (CDCl₃) δ (ppm); 1.07 (3H, br-s), 1.17 (3H, br-s), 1.24(2H, m), 2.26 (2H, m), 2.54 (2H, m), 2.85 (2H, m), 3.05 (2H, m), 3.21(2H, br-s), 3.48 (2H, br-s), 3.95 (3H, s), 4.02 (2H, s), 4.12 (2H, m),4.45 (1H, m), 4.90 (2H, s), 6.71 (1H, m), 6.90 (2H, m), 7.12-7.34 (8H,m)

[0714] MS (TSP); m/z 571 (MH⁺)

Example 881-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]-4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)-3-methylpiperidine

[0715] The title compound was obtained in the same manner in Example 1from the 1-[2-(4-diethylcarbamoylbenzyl)phenoxy]acetaldehyde obtained inReference Example 2 and4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)-3-methylpiperidine synthesizedin accordance with the descriptions of WO98/54168 and U.S. Pat. No.5,756,508. Yield: 10%.

[0716]¹H-NMR (CDCl₃) δ (ppm); 1.00-1.40 (9H, m), 1.79 (1H, d, J=12 Hz),2.20-2.40 (2H, m), 2.54 (1H, d, J=12 Hz), 2.75-2.90 (3H, m), 3.05 (1H,m), 3.10-3.35 (3H, m), 3.48 (2H, br-s), 4.00 (2H, s), 4.10 (2H, d, J=5Hz), 4.39 (1H, dt, J=12 Hz, 3 Hz), 6.85-6.95 (2H, m), 7.00-7.15 (4H, m),7.15-7.30 (6H, m), 9.95 (1H, s)

[0717] MS (TSP); m/z 541 (MH⁺)

Example 891-[2-[2-(4-Diethylaminosulfonylbenzyl)phenoxy]ethyl]-4-(2-hydroxymethyl-1H-benzimidazol-1-yl)piperidine

[0718] The title compound was obtained in the same manner in Example 1from 1-[2-(4-diethylaminosulfonylbenzyl)phenoxy]acetaldehyde obtained inthe same manner in Reference Example 2 and4-(2-hydroxymethyl-1H-benzimidazol-1-yl)piperidine obtained in the samemanner in Reference Example 6. Yield: 57%.

[0719]¹H-NMR (CDCl₃) δ (ppm); 1.08 (6H, t, J=7 Hz), 1.85 (2H, m), 2.26(2H, m), 2.53 (2H, m), 2.81 (2H, t, J=5 Hz), 3.08 (2H, m), 3.17 (4H, q,J=7 Hz), 4.05 (2H, s), 4.12 (2H, t, J=5 Hz), 4.40 (1H, m), 4.90 (2H, s),6.90 (1H, d, J=8 Hz), 6.94 (1H, t, J=8 Hz), 7.13 (1H, d, J=8 Hz),7.20-7.27 (3H, m), 7.31 (2H, d, J=8 Hz), 7.61 (1H, m), 7.67 (2H, d, J=8Hz), 7.70 (1H, m)

[0720] MS (TSP); m/z 577 (MH⁺)

Example 901-[2-[2-(4-Diethylaminosulfonylbenzyl)phenoxy]ethyl]-4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine

[0721] The title compound was obtained in the same manner in Example 1from 1-[2-(4-diethylaminosulfonylbenzyl)phenoxy]acetaldehyde obtained inthe same manner in Reference Example 2 and4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine. Yield: 48%.

[0722]¹H-NMR (CDCl₃) δ (ppm); 1.09 (6H, t, J=7 Hz), 1.80 (2H, m), 2.31(2H, m), 2.48 (2H, m), 2.81 (2H, m), 3.12 (2H, m), 3.19 (4H, q, J=7 Hz),4.04 (2H, s), 4.13 (2H, m), 4.36 (1H, m), 6.90 (2H, m), 7.05 (2H, m),7.09 (2H, m), 7.23 (2H, m), 7.32 (2H, d, J=8 Hz), 7.69 (2H, d, J=8 Hz),9.87 (1H, s)

[0723] MS (TSP); m/z 563 (MH⁺)

Example 918-[2-[2-(4-Diethylaminosulfonylbenzyl)phenoxy]ethyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one

[0724] The title compound was obtained in the same manner in Example 1from 1-[2-(4-diethylaminosulfonylbenzyl)phenoxy]acetaldehyde obtained inthe same manner in Reference Example 2 and1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one. Yield: 44%.

[0725]¹H-NMR (CDCl₃) δ (ppm); 1.11 (6H, t, J=7 Hz), 1.66 (2H, m), 1.80(2H, m), 2.59 (2H, m), 2.82-2.94 (4H, m), 3.18 (4H, q, J=7 Hz), 4.03(2H, s), 4.12 (2H, m), 4.72 (2H, s), 6.83-6.93 (5H, m), 7.11 (1H, d, J=8Hz), 7.24 (4H, m), 7.30 (2H, d, J=8 Hz), 7.66 (2H, d, J=8 Hz)

[0726] MS (TSP); m/z 577 (MH⁺)

Example 921-[2-[2-(3-Diethylaminosulfonylbenzyl)phenoxy]ethyl]-4-(2-hydroxymethyl-1H-benzimidazol-1-yl)piperidine

[0727] The title compound was obtained in the same manner in Example 1from 1-[2-(3-diethylaminosulfonylbenzyl)phenoxy]acetaldehyde obtained inthe same manner in Reference Example 2 and4-(2-hydroxymethyl-1H-benzimidazol-1-yl)piperidine obtained in the samemanner in Reference Example 6. Yield: 25%.

[0728]¹H-NMR (CDCl₃) δ (ppm); 1.09 (6H, t, J=7 Hz), 1.85 (2H, m), 2.27(2H, m), 2.51 (2H, m), 2.85 (2H, t, J=5 Hz), 3.05 (2H, m), 3.20 (4H, q,J=7 Hz), 4.05 (2H, s), 4.12 (2H, t, J=5 Hz), 4.38 (1H, m), 4.91 (2H, s),6.88 (1H, d, J=8 Hz), 6.94 (1H, t, J=8 Hz), 7.15 (1H, d, J=8 Hz), 7.23(3H, m), 7.35 (2H, m), 7.60 (2H, m), 7.70 (2H, s)

[0729] MS (TSP); m/z 577 (MH⁺)

Example 931-[2-[2-(3-Diethylaminosulfonylbenzyl)phenoxy]ethyl]-4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine

[0730] The title compound was obtained in the same manner in Example 1from 1-[2-(3-diethylaminosulfonylbenzyl)phenoxy]acetaldehyde obtained inthe same manner in Reference Example 2 and4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine. Yield: 31%.

[0731]¹H-NMR (CDCl₃) δ (ppm); 1.08 (6H, t, J=7 Hz), 1.83 (2H, m), 2.32(2H, m), 2.48 (2H, m), 2.85 (2H, m), 3.12 (2H, m), 3.19 (4H, q, J=7 Hz),4.04 (2H, s), 4.12 (2H, m), 4.36 (1H, m), 6.90 (2H, m), 7.04 (2H, m),7.10 (2H, m), 7.21 (2H, m), 7.38 (2H, m), 7.60 (1H, d, J=8 Hz), 7.68(1H, s), 9.95 (1H, s)

[0732] MS (TSP); m/z 563 (MH⁺)

Example 948-[2-[2-(3-Diethylaminosulfonylbenzyl)phenoxy]ethyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one

[0733] The title compound was obtained in the same manner in Example 1from 1-[2-(3-diethylaminosulfonylbenzyl)phenoxy]acetaldehyde obtained inthe same manner in Reference Example 2 and1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one. Yield: 33%.

[0734]¹H-NMR (CDCl₃) δ (ppm); 1.06 (6H, t, J=7 Hz), 1.71 (2H, m), 2.64(2H, m), 2.86 (4H, m), 2.96 (2H, m), 3.18 (4H, q, J=7 Hz), 4.04 (2H, s),4.12 (2H, m), 4.73 (2H, s), 6.84-6.92 (6H, m), 7.08 (1H, d, J=8 Hz),7.19-7.28 (3H, m), 7.34 (1H, t, J=8 Hz), 7.40 (1H, d, J=8 Hz), 7.59 (1H,d, J=8 Hz), 7.67 (1H, s)

[0735] MS (TSP); m/z 577 (MH⁺)

Example 951-[2-[2-[(5-Diethylcarbamoylfuran-2-yl)methyl]phenoxy]ethyl]-4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine

[0736] The title compound was obtained in the same manner in Example 1from 1-[2-[(5-diethylcarbamoylfuran-2-yl)methyl]phenoxy]acetaldehydeobtained in the same manner in Reference Example 2 and4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine. Yield: 55%.

[0737]¹H-NMR (CDCl₃) δ (ppm); 1.16 (6H, t, J=7 Hz), 1.81 (2H, d, J=12Hz), 2.35 (2H, t, J=12 Hz), 2.50 (2H, q, J=12 Hz), 2.87 (2H, t, J=5 Hz),3.15 (2H, d, J=12 Hz), 3.47 (4H, q, J=7 Hz), 4.03 (2H, s), 4.15 (2H, t,J=5 Hz), 4.38 (1H, m), 6.10 (1H, d, J=3 Hz), 6.85-6.95 (3H, m),7.00-7.30 (6H, m), 10.00 (1H, s)

[0738] MS (TSP); m/z 517 (MH⁺)

Example 968-[2-[2-[(5-Diethylcarbamoylfuran-2-yl)methyl]phenoxy]ethyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one

[0739] The title compound was obtained in the same manner in Example 1from 1-[2-[(5-diethylcarbamoylfuran-2-yl)methyl]phenoxy]acetaldehydeobtained in the same manner in Reference Example 2 and1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one. Yield: 48%.

[0740]¹H-NMR (CDCl₃) δ (ppm); 1.16 (6H, t, J=7 Hz), 1.72 (2H, d, J=12Hz), 2.67 (2H, m), 2.80-3.10 (6H, m), 3.47 (4H, q, J=7 Hz), 4.02 (2H,s), 4.15 (2H, t, J=5 Hz), 4.73 (2H, s), 6.09 (1H, d, J=3 Hz), 6.80-6.95(6H, m), 7.10-7.30 (5H, m)

[0741] MS (TSP); m/z 531 (MH⁺)

Example 971-[2-[2-[(5-Diethylcarbamoylfuran-2-yl)methyl]phenoxy]ethyl]-4-(2-hydroxymethyl-1H-benzimidazol-1-yl)piperidine

[0742] The title compound obtained in the same manner in Example 1 from1-[2-[(5-diethylcarbamoylfuran-2-yl)methyl]phenoxy]acetaldehyde obtainedin the same manner in Reference Example 2 and4-(2-hydroxymethyl-1H-benzimidazol-1-yl)piperidine obtained in the samemanner in Reference Example 6. Yield: 50%.

[0743]¹H-NMR (CDCl₃) δ (ppm); 1.13 (6H, t, J=7 Hz), 1.87 (2H, d, J=12Hz), 2.31 (2H, t, J=12 Hz), 2.53 (2H, q, J=12 Hz), 2.89 (2H, t, J=5 Hz),3.11 (2H, d, J=12 Hz), 3.45 (4H, q, J=7 Hz), 4.02 (2H, s), 4.15 (2H, t,J=5 Hz), 4.46 (1H, m), 4.89 (2H, s), 6.04 (1H, d, J=3 Hz), 6.85-6.95(3H, m), 7.15-7.30 (4H, m), 7.55-7.85 (2H, m)

[0744] MS (TSP); m/z 531 (MH⁺)

Example 981′-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]-2,3-dihydro-5-methoxyspiro[isoquinoline-4(1H),4′-piperidin]-1-one

[0745] The title compound was obtained in the same manner in Example 1from the 1-[2-(4-diethylcarbamoylbenzyl)phenoxy]acetaldehyde obtained inReference Example 2 and2,3-dihydro-5-methoxyspiro[isoquinoline-4(1H),4′-piperidin]-1-onetrifluoroacetate obtained in the same manner in Reference Example 12.Yield: 53%.

[0746]¹H-NMR (CDCl₃) δ (ppm); 1.10 (3H, br-s), 1.22 (3H, br-s), 1.59(2H, d, J=12 Hz), 2.25 (2H, t, J=12 Hz), 2.75-2.95 (6H, m), 3.24 (2H,br-s), 3.45-3.60 (4H, m), 3.84 (3H, s), 3.99 (2H, s), 4.15 (2H, t, J=5Hz), 6.48 (1H, br-s), 6.85-6.95 (2H, m), 7.02 (1H, d, J=8 Hz), 7.13 (1H,d, J=8 Hz), 7.15-7.35 (6H, m), 7.78 (1H, m)

[0747] MS (FAB); m/z 556 (MH⁺)

Example 991-[2-[2-(4-Diethylaminomethylbenzyl)phenoxy]ethyl]-4-(2-hydroxymethyl-1H-benzimidazol-1-yl)piperidine

[0748] The1-[2-[2-(4-diethylcarbamoylbenzyl)phenoxy]ethyl]-4-(2-hydroxymethyl-1H-benzimidazol-1-yl)piperidine(64 mg) obtained in Example 84 was dissolved in tetrahydrofuran (1.3ml), added with a solution of Red-Al in toluene (65%, 0.18 ml) andstirred at room temperature for 2.5 hours. After the reaction mixturewas slowly poured into ice 10 g with ice cooling to quench the reactionand the layers were separated, the aqueous layer was extracted withdichloromethane (30 ml). The organic layer was dried over anhydrousmagnesium sulfate, and then the solvent was evaporated under reducedpressure. The residue was purified by preparative thin layer silica gelcolumn chromatography (developing solvent:dichloromethane:methanol:aqueous ammonia=9:1:0.1) to obtain 31 mg of thetitle compound. Yield: 50%.

[0749]¹H-NMR (CDCl₃) δ (ppm); 0.99 (6H, t, J=7 Hz), 1.75 (2H, d, J=12Hz), 2.28 (2H, t, J=12 Hz), 2.40-2.60 (6H, m), 2.91 (2H, t, J=5 Hz),3.03 (2H, d, J=12 Hz), 3.55 (2H, s), 4.00 (2H, s), 4.13 (2H, d, J=5 Hz),4.42 (1H, m), 4.90 (2H, s), 6.87 (1H, d, J=8 Hz), 6.92 (1H, t, J=8 Hz),7.10-7.30 (8H, m), 7.60 (1H, m), 7.69 (1H, m)

[0750] MS (TSP); m/z 527 (MH⁺)

Example 1001-[2-[2-(4-Diethylcarbamoylbenzyl)phenoxy]ethyl]-4-(2-hydroxymethyl-1H-benzimidazol-1-yl)-3-methylpiperidine

[0751] The title compound was obtained in the same manner in Example 1from the 1-[2-(4-diethylcarbamoylbenzyl)phenoxy]acetaldehyde obtained inReference Example 2 and4-(2-hydroxymethyl-1H-benzimidazol-1-yl)-3-methylpiperidine obtained inthe same manner in Reference Example 13. Yield: 13%.

[0752]¹H-NMR (CDCl₃) δ (ppm); 1.07 (6H, m), 1.17 (3H, br-s), 1.80 (1H,d, J=12 Hz), 2.24 (2H, t, J=12 Hz), 2.42 (1H, d, J=12 Hz), 2.70-3.00(4H, m), 3.12 (1H, d, J=12 Hz), 3.23 (2H, br-s), 3.47 (2H, br-s),3.95-4.15 (4H, m), 4.58 (1H, dt, J=12 Hz, 5 Hz), 4.86 (1H, d, J=14 Hz),4.92 (1H, d, J=14 Hz), 6.88 (1H, d, J=8 Hz), 6.92 (1H, t, J=8 Hz),7.10-7.30 (8H, m), 7.51 (1H, m), 7.67 (1H, m)

[0753] MS (TSP); m/z 555 (MH⁺)

Example 1011-[2-[2-(3-Diethylcarbamoylbenzyl)phenoxy]ethyl]-4-(2-hydroxymethyl-1H-benzimidazol-1-yl)piperidine

[0754] The title compound was obtained in the same manner in Example 1from 1-[2-(3-diethylcarbamoylbenzyl)phenoxy]acetaldehyde obtained in thesame manner in Reference Example 2 and4-(2-hydroxymethyl-1H-benzimidazol-1-yl)piperidine obtained in the samemanner in Reference Example 6. Yield: 55%.

[0755]¹H-NMR (CDCl₃) δ (ppm); 1.03 (3H, br-s), 1.21 (3H, br-s), 1.80(2H, d, J=12 Hz), 2.22 (2H, t, J=12 Hz), 2.48 (2H, q, J=12 Hz), 2.87(2H, t, J=5 Hz), 3.00 (2H, d, J=12 Hz), 3.19 (2H, br-s), 3.50 (2H,br-s), 4.02 (2H, s), 4.12 (2H, t, J=5 Hz), 4.42 (1H, m), 4.89 (2H, s),6.80-6.95 (2H, m), 7.10-7.30 (8H, m), 7.55-7.85 (2H, m)

[0756] MS (TSP); m/z 541 (MH⁺)

Example 1021-[2-[2-(3-Diethylcarbamoylbenzyl)phenoxy]ethyl]-4-(2-hydroxymethyl-7-methyl-i1H-benzimidazol-1-yl)piperidine

[0757] The title compound was obtained in the same manner in Example 1from 1-[2-(3-diethylcarbamoylbenzyl)phenoxy]acetaldehyde obtained in thesame manner in Reference Example 2 and the4-(2-hydroxymethyl-7-methyl-1H-benzimidazol-1-yl)piperidine obtained inReference Example 13. Yield: 45%.

[0758]¹H-NMR (CDCl₃) δ (ppm); 1.02 (3H, br-s), 1.22 (3H, br-s), 1.78(2H, d, J=12 Hz), 2.22 (2H, t, J=12 Hz), 2.48 (2H, q, J=12 Hz), 2.62(3H, s), 2.87 (2H, t, J=5 Hz), 3.00 (2H, d, J=12 Hz), 3.17 (2H, br-s),3.49 (2H, br-s), 4.02 (2H, s), 4.12 (2H, t, J=5 Hz), 4.43 (1H, m), 4.93(2H, s), 6.80-7.30 (10H, m), 7.45 (1H, d, J=8 Hz)

[0759] MS (TSP); m/z 555 (MH⁺)

Example 1031-[2-[2-(4-Isobutyloxycarbonylbenzyl)phenoxy]ethyl]-4-(2-hydroxymethyl-1H-benzimidazol-1-yl)piperidine

[0760] The title compound was obtained in the same manner in Example 1from the 1-[2-(4-isobutyloxycarbonylbenzyl)phenoxy]acetaldehyde obtainedin Reference Example 14 and4-(2-hydroxymethyl-1H-benzimidazol-1-yl)piperidine obtained in the samemanner in Reference Example 6. Yield: 40%.

[0761]¹H-NMR (CDCl₃) δ (ppm); 0.91 (6H, m), 1.83 (2H, m), 1.94 (1H, m),2.29 (2H, m), 2.50 (2H, m), 2.83 (2H, m), 3.06 (2H, m), 3.99 (2H, m),4.05 (2H, s), 4.12 (2H, m), 4.41 (1H, m), 4.86 (2H, s), 6.90 (2H, m),7.20 (6H, m), 7.59 (1H, m), 7.68 (1H, m), 7.92 (2H, m)

[0762] MS (FAB); m/z 542 (MH⁺)

Example 1041-[2-[2-(4-Isobutyloxycarbonylbenzyl)phenoxy]ethyl]-4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine

[0763] The title compound was obtained from the1-[2-(4-isobutyloxycarbonylbenzyl)phenoxy]acetaldehyde obtained inReference Example 14 and4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine in the same mannerin Example 1. Yield: 43%.

[0764]¹H-NMR (CDCl₃) δ (ppm); 0.96 (6H, m), 1.80 (2H, m), 2.05 (1H, m),2.31 (2H, m), 2.47 (2H, m), 2.82 (2H, m), 3.10 (2H, m), 4.04 (4H, m),4.12 (2H, m), 4.36 (1H, m), 6.90 (2H, m), 7.04 (2H, m), 7.10 (2H, m),7.25 (4H, m), 7.95 (2H, m), 9.99 (1H, s)

[0765] MS (FAB); m/z 528 (MH⁺)

Example 1058-[2-[2-(4-Isobutyloxycarbonylbenzyl)phenoxy]ethyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one

[0766] The title compound was obtained in the same manner in Example 1from the 1-[2-(4-isobutyloxycarbonylbenzyl)phenoxy]acetaldehyde obtainedin Reference Example 14 and 1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one.Yield: 46%.

[0767]¹H-NMR (CDCl₃) δ (ppm); 0.99 (6H, m), 1.69 (2H, m), 2.04 (1H, m),2.64 (2H, m), 2.85 (4H, m), 2.94 (2H, m), 4.04 (4H, m), 4.12 (2H, m),4.72 (2H, s), 6.89 (5H, m), 7.10 (1H, m), 7.26 (6H, m), 7.92 (2H, d, J=8Hz)

[0768] MS (TSP); m/z 542 (MH⁺)

Example 1061-[2-[2-(4-Carboxybenzyl)phenoxy]ethyl]-4-(2-hydroxymethyl-1H-benzimidazol-1-yl)piperidine

[0769] The1-[2-[2-(4-isobutyloxycarbonylbenzyl)phenoxy]ethyl]-4-(2-hydroxymethyl-1H-benzimidazol-1-yl)piperidine(49 mg) obtained in Example 103 was dissolved in methanol (0.5 ml),added with 1 N aqueous sodium hydroxide (0.18 ml) and stirred at 50° C.for 2.5 hours. After the reaction mixture was added with 1 N aqueoushydrochloric acid (0.72 ml), the solvent was evaporated under reducedpressure. The residue was purified by LH-20 column chromatography(elution solvent: dichloromethane:methanol=1:1) to obtain 48.3 mg of thetitle compound as hydrochloride. Yield: 100%.

[0770]¹H-NMR (CDCl₃) δ (ppm); 2.15 (2H, m), 2.95 (2H, m), 3.30 (2H, m),3.56 (2H, m), 3.68 (2H, m), 4.11 (2H, s), 4.45 (2H, m), 4.88 (1H, m),5.19 (2H, s), 6.89 (1H, t, J=8 Hz), 7.04 (1H, d, J=8 Hz), 7.18 (1H, d,J=8 Hz), 7.24 (3H, m), 7.59 (2H, m), 7.78 (1H, m), 7.84 (2H, d, J=8 Hz),8.29 (1H, m)

[0771] MS (TSP); m/z 486 (MH⁺)

Example 1071-[2-[2-[trans-(4-Diethylcarbamoylcyclohexyl)methyl]phenoxy]ethyl]-4(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine

[0772] The title compound was obtained in the same manner in Example 1from1-[2-[trans-(4-diethylcarbamoylcyclohexyl)methyl]phenoxy]acetaldehydeobtained in the same manner in Reference Example 2 and4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine. Yield: 65%.

[0773]¹H-NMR (CDCl₃) δ (ppm); 1.02 (2H, m), 1.07 (3H, t, J=7 Hz), 1.15(3H, t, J=7 Hz), 1.45-1.90 (9H, m), 2.30-2.60 (7H, m), 2.90 (2H, t, J=5Hz), 3.15-3.40 (6H, m), 4.15 (2H, t, J=5 Hz), 4.41 (1H, m), 6.80-6.90(2H, m), 7.00-7.35 (6H, m), 9.53 (1H, s)

[0774] MS (TSP); m/z 533 (MH⁺)

Example 1088-[2-[2-[trans-(4-Diethylcarbamoylcyclohexyl)methyl]phenoxy]ethyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one

[0775] The title compound was obtained in the same manner in Example 1from1-[2-[trans-(4-diethylcarbamoylcyclohexyl)methyl]phenoxy]acetaldehydeobtained in the same manner in Reference Example 2 and1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one. Yield: 53%.

[0776]¹H-NMR (CDCl₃) δ (ppm); 1.02 (2H, m), 1.07 (3H, t, J=7 Hz), 1.15(3H, t, J=7 Hz), 1.45-1.80 (9H, m), 2.35 (1H, m), 2.51 (2H, d, J=7 Hz),2.70 (2H, m), 2.95 (4H, m), 3.12 (2H, m), 3.40 (4H, m), 4.15 (2H, t, J=5Hz), 4.72 (2H, s), 6.80-6.95 (5H, m), 7.04 (2H, m), 7.15 (1H, m), 7.27(2H, m)

[0777] MS (TSP); m/z 547 (MH⁺)

Example 1091-[2-[2-[trans-(4-Diethylcarbamoylcyclohexyl)methyl]phenoxy]ethyl]-4-(2-hydroxymethyl-1H-benzimidazol-1-yl)piperidine

[0778] The title compound was obtained in the same manner in Example 1from1-[2-[trans-(4-diethylcarbamoylcyclohexyl)methyl]phenoxy]acetaldehydeobtained in the same manner in Reference Example 2 and4-(2-hydroxymethyl-1H-benzimidazol-1-yl)piperidine obtained in the samemanner in Reference Example 6. Yield: 66%.

[0779]¹H-NMR (CDCl₃) δ (ppm); 1.02 (2H, m), 1.07 (3H, t, J=7 Hz), 1.15(3H, t, J=7 Hz), 1.45-1.80 (7H, m), 1.97 (2H, m), 2.45-2.70 (6H, m),3.03 (2H, t, J=5 Hz), 3.15-3.40 (6H, m), 4.15 (2H, t, J=5 Hz), 4.72 (1H,m), 4.94 (2H, s), 6.80-6.90 (2H, m), 7.04 (1H d, J=8 Hz), 7.15-7.30 (3H,m), 7.60-7.75 (2H, m)

[0780] MS (TSP); m/z 547 (MH⁺)

Example 1104-(2-Hydroxymethyl-1H-benzimidazol-1-yl)-1-[2-[2-[4-(2-methylbutyryl)benzyl]phenoxy]ethyl]piperidine

[0781] The title compound was obtained in the same manner in Example 1from the 1-[2-[4-(2-methylbutyryl)benzyl]phenoxy]acetaldehyde obtainedin Reference Example 15 and4-(2-hydroxymethyl-1H-benzimidazol-1-yl)piperidine obtained in the samemanner in Reference Example 6. Yield: 59%.

[0782]¹H-NMR (CDCl₃) δ (ppm); 0.81 (3H, t, J=7 Hz), 1.10 (3H, d, J=7Hz), 1.40 (1H, m), 1.74 (1H, m), 1.83 (2H, m), 2.30 (2H, m), 2.50 (2H,m), 2.84 (2H, m), 3.09 (2H, m), 3.30 (1H, m), 4.06 (2H, s), 4.15 (2H,m), 4.40 (1H, m), 4.88 (2H, s), 6.91 (2H, m), 7.14 (1H, m), 7.25 (5H,m), 7.60 (1H, m), 7.68 (1H, m), 7.84 (2H, d, J=8 Hz)

[0783] MS (FAB); m/z 526 (MH⁺)

Example 1111-[2-[2-[cis-(4-Diethylcarbamoylcyclohexyl)methyl]phenoxy]ethyl]-4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine

[0784] The title compound was obtained in the same manner in Example 1from 1-[2-[cis-(4-diethylcarbamoylcyclohexyl)methyl]phenoxy]acetaldehydeobtained in the same manner in Reference Example 2 and4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine. Yield: 51%.

[0785]¹H-NMR (CDCl₃) δ (ppm); 1.10 (3H, t, J=7 Hz), 1.16 (3H, t, J=7Hz), 1.48 (4H, m), 1.65 (1H, m), 1.75-2.00 (6H, m), 2.35-2.60 (5H, m),2.72 (2H, d, J=7 Hz), 2.91 (2H, t, J=5 Hz), 3.15-3.40 (6H, m), 4.14 (2H,t, J=5 Hz), 4.41 (1H, m), 6.80-6.90 (2H, m), 7.00-7.20 (4H, m),7.25-7.35 (2H, m), 9.83 (1H, s)

[0786] MS (TSP); m/z 533 (MH⁺)

Example 1128-[2-[2-[cis-(4-Diethylcarbamoylcyclohexyl)methyl]phenoxy]ethyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one

[0787] The title compound was obtained in the same manner in Example 1from 1-[2-[cis-(4-diethylcarbamoylcyclohexyl)methyl]phenoxy]acetaldehydeobtained in the same manner in Reference Example 2 and1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one. Yield: 39%.

[0788]¹H-NMR (CDCl₃) δ (ppm); 1.10 (3H, t, J=7 Hz), 1.16 (3H, t, J=7Hz), 1.40-1.50 (4H, m), 1.55-2.05 (8H, m), 2.47 (1H, m), 2.70 (3H, m),2.95-3.10 (6H, m), 3.25-3.40 (4H, m), 4.15 (2H, m), 4.74 (2H, s),6.80-6.95 (2H, m), 7.05-7.20 (3H, m), 7.25-7.35 (5H, m)

[0789] MS (TSP); m/z 547 (MH⁺)

Example 1131-[2-[2-[cis-(4-Diethylcarbamoylcyclohexyl)methyl]phenoxy]ethyl]-4-(2-hydroxymethyl-1H-benzimidazol-1-yl)piperidine

[0790] The title compound was obtained in the same manner in Example 1from 1-[2-[cis-(4-diethylcarbamoylcyclohexyl)methyl]phenoxy]acetaldehydeobtained in the same manner in Reference Example 2 and4-(2-hydroxymethyl-1H-benzimidazol-1-yl)piperidine obtained in the samemanner in Reference Example 6. Yield: 57%.

[0791]¹H-NMR (CDCl₃) δ (ppm); 1.07 (3H, t, J=7 Hz), 1.16 (3H, t, J=7Hz), 1.48 (4H, m), 1.64 (1H, m), 1.80-2.10 (5H, m), 2.40-2.70 (6H, m),2.73 (2H, d, J=7 Hz), 2.94 (2H, t, J=5 Hz), 3.20-3.40 (6H, m), 4.15 (2H,t, J=5 Hz), 4.54 (1H, m), 4.87 (2H, s), 6.80-6.95 (2H, m), 7.10-7.25(4H, m), 7.60-7.75 (2H, m)

[0792] MS (TSP); m/z 547 (MH⁺)

Example 1142-Benzyl-1′-[2-[2-(4-diethylcarbamoylbenzyl)phenoxy]ethyl]2,3-dihydrospiro[isoquinoline-4(1H),4′-piperidin]-1-one

[0793] The title compound was obtained in the same manner in Example 1from the 1-[2-(4-diethylcarbamoylbenzyl)phenoxy]acetaldehyde obtained inReference Example 2 and the2-benzyl-2,3-dihydrospiro[isoquinoline-4(1H),4′-piperidin]-1-oneobtained in Reference Example 16. Yield: 60%.

[0794]¹H-NMR (CDCl₃) δ (ppm); 1.10 (3H, br-s), 1.21 (3H, br-s), 1.49(2H, d, J=14 Hz), 1.80 (2H, m), 2.48 (2H, td, J=14 Hz, 4 Hz), 2.58 (3H,s), 2.63 (2H, t, J=5 Hz), 2.70 (2H, m), 3.25 (2H, br-s), 3.45 (2H, s),3.51 (2H, br-s), 3.97 (2H, s), 4.00 (2H, t, J=5 Hz), 4.75 (2H, s),6.80-6.95 (2H, m), 7.08 (1H, d, J=8 Hz), 7.15-7.40 (12H, m), 8.11 (1H,t, J=8 Hz)

[0795] MS (FAB); m/z 630 (MH⁺)

Example 1152-(4-Diethylcarbamoylbenzyl)-1′-[2-[2-(4-diethylcarbamoylbenzyl)phenoxy]ethyl]-2,3-dihydrospiro[isoquinoline-4(1H),4′-piperidin]-1-one

[0796] The title compound was obtained in the same manner in Example 1from the 1-[2-(4-diethylcarbamoylbenzyl)phenoxy]acetaldehyde obtained inReference Example 2 and2-(4-diethylcarbamoylbenzyl)-2,3-dihydrospiro[isoquinoline-4(1H),4′-piperidin]-1-oneobtained in the same manner in Reference Example 16. Yield: 24%.

[0797]¹H-NMR (CDCl₃) δ (ppm); 1.10 (6H, br-s), 1.22 (6H, br-s), 1.52(2H, d, J=14 Hz), 1.95 (2H, m), 2.54 (2H, m), 2.59 (3H, s), 2.70 (4H,m), 3.24 (4H, br-s), 3.45 (2H, s), 3.52 (4H, br-s), 4.03 (2H, s), 4.05(2H, t, J=5 Hz), 4.79 (2H, s), 6.90 (2H, t, J=8 Hz), 7.09 (1H, d, J=8Hz), 7.15-7.40 (11H, m), 8.11 (1H, m)

[0798] MS (TSP); m/z 729 (MH⁺)

Example 1162-Cyclopropylmethyl-1′-[2-[2-(4-diethylcarbamoylbenzyl)phenoxy]ethyl]-2,3-dihydrospiro[isoquinoline-4(1H),4′-piperidin]-1-one

[0799] The title compound was obtained in the same manner in Example 1from the 1-[2-(4-diethylcarbamoylbenzyl)phenoxy]acetaldehyde obtained inReference Example 2 and2-cyclopropylmethyl-2,3-dihydrospiro[isoquinoline-4(1H),4′-piperidin]-1-oneobtained in the same manner in Reference Example 16. Yield: 61%.

[0800]¹H-NMR (CDCl₃) δ (ppm); 0.34 (2H, m), 0.55 (2H, m), 1.00-1.30 (7H,m), 1.69 (2H, d, J=14 Hz), 2.39 (2H, t, J-14 Hz), 2.62 (3H, s), 2.64(2H, m), 2.82 (2H, t, J=5 Hz), 2.92 (2H, d, J=14 Hz), 3.25 (2H, br-s),3.45 (2H, d, J=7 Hz), 3.50 (2H, br-s), 3.64 (2H, s), 3.99 (2H, s), 4.13(2H, t, J=5 Hz), 6.85-6.95 (2H, m), 7.09 (1H, d, J=8 Hz), 7.15-7.30 (7H,m), 8.04 (1H, m)

[0801] MS (TSP); m/z 594 (MH⁺)

Example 1172-(3-Diethylcarbamoylbenzyl)-1′-[2-[2-(4-diethylcarbamoylbenzyl)phenoxy]ethyl]-2,3-dihydrospiro[isoquinoline-4(1H),4′-piperidin]-1-one

[0802] The title compound was obtained in the same manner in Example 1from the 1-[2-(4-diethylcarbamoylbenzyl)phenoxy]acetaldehyde obtained inReference Example 2 and2-(3-diethylcarbamoylbenzyl)-2,3-dihydrospiro[isoquinoline-4(1H),4′-piperidin]-1-oneobtained in the same manner in Reference Example 16. Yield: 56%.

[0803]¹H-NMR (CDCl₃) δ (ppm); 1.09 (6H, br-s), 1.22 (6H, br-s), 1.53(2H, d, J=14 Hz), 1.93 (2H, m), 2.53 (2H, m), 2.59 (3H, s), 2.71 (4H,m), 3.23 (4H, br-s), 3.47 (2H, s), 3.51 (4H, br-s), 3.97 (2H, s), 4.05(2H, t, J=5 Hz), 4.79 (2H, s), 6.85-6.95 (2H, m), 7.09 (1H, d, J=8 Hz),7.15-7.40 (11H, m), 8.11 (1H, m)

[0804] MS (TSP); m/z 729 (MH⁺)

Example 1184-(N-Acetylanilino)-1-[2-[2-(4-diethylcarbamoylbenzyl)phenoxy]ethyl]piperidine

[0805] The title compound was obtained in the same manner in Example 1from the 1-[2-(4-diethylcarbamoylbenzyl)phenoxy]acetaldehyde obtained inReference Example 2 and 4-(N-acetylanilino)piperidine. Yield: 73%.

[0806]¹H-NMR (CDCl₃) δ (ppm); 1.12 (3H, br-s), 1.22 (3H, br-s), 1.40(2H, qd, J=12 Hz, 4 Hz), 1.74 (3H, s), 1.77 (2H, d, J=12 Hz), 2.27 (2H,t, J=12 Hz), 2.72 (2H, t, J=5 Hz), 2.97 (2H, d, J=12 Hz), 3.27 (2H,br-s), 3.53 (2H, br-s), 3.94 (2H, s), 4.00 (2H, t, J=5 Hz), 4.65 (1H,m), 6.79 (1H, d, J=8 Hz), 6.86 (1H, t, J=8 Hz), 7.00-7.45 (11H, m)

[0807] MS (FAB); m/z 528 (MH⁺)

Test Example 1 Binding Affinity for Opioid δ Receptor

[0808] A membrane fraction of opioid δ receptor was prepared from therat forebrain. For the preparation of the membrane fraction, the ratforebrain was homogenized in a 10-fold volume of 0.32 M sucrosesolution, and the resulting homogenate was centrifuged at 900×g for 10minutes. Subsequently, the supernatant was centrifuged at 11,500×g for20 minutes to obtain precipitates. The precipitates were washed with anassay buffer (50 mM Tris-HCl, pH 7.4) by centrifugation, and the finallyobtained membrane fraction was used for the experiment.

[0809] A binding experiment was performed by using the resultingmembrane fraction and a radioactive ligand [³H]-Naltrindole. In thepresence of a test compound, the membrane fraction and [³H]-Naltrindoleat a final concentration of 1 nM were added and incubated at 25° C. for90 minutes. The membrane fraction mixture was rapidly filtered through aGF/B filter to quench the reaction and further washed with the assaybuffer (5 ml). The radioactivity was measured by a liquid scintillationcounter. Amount of non-specific bindings was determined by using 10 μMNaltrindole, and amount of specific bindings was calculated from thedifference of the amounts of measured bindings and the non-specificbindings. IC₅₀ value of each compound was determined by nonlinear leastsquare regression analysis, and Ki value was calculated by using theCheng-Prusoff equation.

[0810] The results of the measurement of opioid δ receptor bindingaffinity of the compounds of the present invention by the above methodare shown in Table 1 below. TABLE 1 Binding affinity Ki (nM) Compound ofExample 15 281 Compound of Example 29 235 Compound of Example 32 517Compound of Example 33 467 Compound of Example 36 240 Compound ofExample 40 243 Compound of Example 49 943 Compound of Example 88 767Compound of Example 103 73 Compound of Example 107 133 Compound ofExample 110 88 Compound of Example 114 1530

INDUSTRIAL APPLICABILITY

[0811] The compounds of the present invention have effective andselective affinity for opioid δ receptors. The provision of medicamentsconsisting the compound described above will greatly contribute totherapeutic treatments of central nerve system diseases includingschizophrenia, depression, cerebral apoplexy, epilepsy, Alzheimer'sdisease and Parkinson's disease and peripheral nerve system diseasesincluding pains.

What is claimed is:
 1. A compound represented by the following generalformula (I) of a salt thereof:

wherein, X represents the following group (II), (III), (IV), (V), or(VI),

“A” represents a saturated or unsaturated 3- to 6-membered carbocyclicgroup or a saturated or unsaturated monocyclic heterocyclic groupcontaining one or more hetero atoms, “B” represents —CH₂—, —CHOH—,—(C═O)—, —CH₂CH₂—, or a single bond, “n” represents 0, 1 or 2, R¹represents a hydrogen atom, a halogen atom, a lower alkyl group whichmay be substituted, a lower alkenyl group which may be substituted, alower alkoxy group which may be substituted, a hydroxy group, a cyanogroup, an amino group, a N,N-di(lower alkyl)amino group, aN,N-di(substituted lower alkyl)amino group, a nitro group, a carbamoylgroup, a N,N-di(lower alkyl)carbamoyl group, a N,N-di(substituted loweralkyl)carbamoyl group, a carboxyl group, a lower alkoxycarbonyl groupwhich may be substituted or a lower alkylcarbonyl group which may besubstituted, R², R³, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, and R¹⁴independently represent a hydrogen atom, a lower alkyl group which maybe substituted or a lower alkenyl group which may be substituted, R⁴represents a hydrogen atom, a lower alkyl group which may besubstituted, a lower alkenyl group which may be substituted, or a loweralkoxy group which may be substituted, R⁵ represents a hydrogen atom, ahalogen atom, a lower alkyl group which may be substituted, a loweralkenyl group which may be substituted, a lower alkoxy group which maybe substituted, a hydroxy group, a cyano group, an amino group, aN,N-di(lower alkyl)amino group, a N,N-di(substituted lower alkyl)aminogroup, a carbamoyl group, a N,N-di(lower alkyl)carbamoyl group, aN,N-di(substituted lower alkyl)carbamoyl group, a carboxyl group, alower alkoxycarbonyl group which may be substituted, or a loweralkylcarbonyl group which may be substituted, R⁶ represents a saturatedor unsaturated monocyclic or bicyclic carbocyclic group, a saturated orunsaturated monocyclic or bicyclic heterocyclic group containing one ormore hetero atoms or a N-(lower alkyl)carbonyl-N-(substituted orunsubstituted phenyl)amino group, and R⁵ and R⁶, R⁷ and R⁸, R⁹ and R¹⁰,or R¹¹ and R¹² may bind to each other to form a cyclic structure.
 2. Thecompound or a salt thereof according to claim 1, wherein R⁶ representsthe following group (VII):

wherein,

represents a single bond or a double bond, R¹⁵ represents a hydrogenatom, a lower alkyl group which may be substituted, a lower alkenylgroup which may be substituted, or oxo group, R¹⁶ represents a hydrogenatom, a halogen atom, a lower alkyl group which may be substituted, alower alkenyl group which may be substituted, a lower alkoxy group whichmay be substituted, a hydroxy group, a cyano group, an amino group, aN,N-di(lower alkyl)amino group, a N,N-di(substituted lower alkyl)aminogroup, a nitro group, a carbamoyl group, a N,N-di(lower alkyl)carbamoylgroup, a N,N-di(substituted lower alkyl)carbamoyl group, carboxyl group,a lower alkoxycarbonyl group which may be substituted, or a loweralkylcarbonyl group which may be substituted.
 3. The compound or a saltthereof according to claim 1, wherein R⁵ and R⁶ bind to each other torepresent the following group (VIII):

wherein, R¹⁷ represents a hydrogen atom, a lower alkyl group which maybe substituted, or a lower alkenyl group which may be substituted, andR¹⁸ represents a hydrogen atom, a halogen atom, a lower alkyl groupwhich may be substituted, a lower alkenyl group which may besubstituted, a lower alkoxy group which may be substituted, hydroxygroup, cyano group, an amino group, an N,N-di(lower alkyl)amino group,an N,N-di(substituted lower alkyl)amino group, nitro group, a carbamoylgroup, an N,N-di(lower alkyl)carbamoyl group, an N,N-di(substitutedlower alkyl)carbamoyl group, carboxyl group, a lower alkoxycarbonylgroup which may be substituted, or a lower alkylcarbonyl group which maybe substituted.
 4. The compound or a salt thereof according to any oneof claims 1 to 3, wherein X represents the group (II), (III), (V), or(VI), “A” represents a residue derived from a ring selected from thegroup consisting of benzene, cyclohexane, and furan, “B” represents—CH₂—, —CHOH—, —(C═O)—, —CH₂CH₂—, or a single bond, “n” represents 0, 1,or 2, R¹ represents a hydrogen atom or a lower alkoxy group, R², R³, R⁷,R⁸, R⁹, R¹⁰, R¹³, and R¹⁴ each independently represent a hydrogen atomor a lower alkyl group which may be substituted, R⁴ represents ahydrogen atom or a lower alkyl group which may be substituted, R⁵represents a hydrogen atom or a lower alkylcarbonyl group which may besubstituted, R⁶ represents a residue of a ring selected from the groupconsisting of benzene, naphthalene, indane, benzofuran, imidazole,benzimidazole, indole, quinoline, benzotriazole, benzimidazole,benzisothiazole, benzisoxazole, quinazoline, isoquinoline andbenzoxazine wherein a hydrogen atom on ring may be replaced withhalogen, oxo, lower alkyl, hydroxymethyl, lower alkoxy or benzyl, or R⁵and R⁶ bind to each other to represent a residue of a ring selected fromthe group consisting of indane, imidazole, N-phenylimidazolidine,isoquinoline, quinoline and benzofuran wherein a hydrogen atom on ringmay be replaced with oxo, lower alkyl or lower alkoxy, and R⁷ and R⁸bind to each other to represent pyrrolidine or piperidine.
 5. Thecompound or a salt thereof according to any one of claims 1 to 4,wherein X represents the group (II).
 6. A medicament comprising asubstance selected from the group consisting of the compound accordingto any one of claims 1 to 5 and a pharmacologically acceptable saltthereof as an active ingredient.
 7. The medicament according to claim 6in a form of a pharmaceutical composition which comprises a substanceselected from the group consisting of the compound according to any oneof claims 1 to 5 and a pharmacologically acceptable salt thereoftogether with a pharamaceutical additive.
 8. The medicament according toclaim 6 or 7, which has affinity for an opioid δ receptor.
 9. Themedicament according to claim 6 or 7, which is used for preventiveand/or therapeutic treatment of a central nerve system disease or aperipheral nerve system disease.
 10. The medicament according to claim9, wherein the central nerve system disease is schizophrenia,depression, cerebral apoplexy, epilepsy, Alzheimer's disease, orParkinson's disease.
 11. The medicament according to claim 9, whereinthe peripheral nerve system disease is pain.
 12. An agent acting on anopioid δ receptor which comprises a substance selected from the groupconsisting of the compound according to any one of claims 1 to 5 and apharmacologically acceptable salt thereof.
 13. Use of a substanceselected from the group consisting of the compound according to any oneof claims 1 to 5 and a pharmacologically acceptable salt thereof formanufacture of the medicament according to any one of claims 6 to 11.14. A method for preventive and/or therapeutic treatment of a centralnerve system disease, which comprises a step of administeringpreventiveally and/or therapeutically effective amount of a substanceselected from the group consisting of the compound according to any oneof claims 1 to 5 and a pharmacologically acceptable salt thereof to amammal including human.
 15. A method for preventive and/or therapeutictreatment of a peripheral nerve system disease, which comprises a stepof administering preventiveally and/or therapeutically effective amountof a substance selected from the group consisting of the compoundaccording to any one of claims 1 to 5 and a pharmacologically acceptablesalt thereof to a mammal including human.